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Pediatric Brain Death Determination M udit Mathur, MD, FAAP1

Stephen Ashwal, MD, FAAP2

1Division of Pediatric Critical Care, Loma Linda University Children's Hospital, Loma Linda, California 2 Division of Pediatric Neurology, Loma Linda University Children’s Hospital, Loma Linda, California

Address for correspondence Mudit Mathur, MD, FAAP, Division of Pediatric Critical Care, Division of Pediatric Critical Care, Loma Linda University Children’s Hospital, 11175 Campus Street, Coleman A1117G, Loma Linda, CA 92350 (e-mail; [email protected]).

Semin Neurol 2015;35:116-124.

Abstract

Clinical guidelines for the determination of brain death in children were first published in 1987. These guidelines were revised in 2011 under the auspices of the Society of Critical Care Medicine, the American Academy of Pediatrics, and the Child Neurology Society, and provide the minimum standards that must be satisfied before brain death can be declared in infants and children. After achieving physiologic stability and exclusion of confounders, two examinations including apnea testing separated by an observation period (24 hours for term newborns up to 30 days of age, and 12 hours for infants and children from 31 days up to 18 years) are required to establish brain death. Apnea testing should demonstrate a final arterial PaC02 20 mm Fig above the baseline and > 60 mm Fig with no respiratory effort during the testing period. Ancillary studies (electroencephalogram and radionuclide cerebral blood flow) are not required to establish brain death and are not a substitute for the neurologic examination. The

Keywords

committee concluded that ancillary studies may be used (1) when components of the

► brain death

examination or apnea testing cannot be completed, (2) if uncertainty about compo­

► infants

nents of the neurologic examination exists, (3) if a medication effect may be present, or

► children ► apnea test

(4) to reduce the interexamination observation period. When ancillary studies are used, a second clinical examination and apnea test should still be performed and components

► ancillary study

that can be completed must remain consistent with brain death.

The American Medical Association and the American Bar Asso­ ciation supported universal enactment of the Uniform Determi­ nation ofDeath Act (UDDA) published in 1980.1This 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." Brain death is legally accepted as death under the UDDA in 45 states and recognized in the rest through judicial opinion. The most recent update to the criteria for the determination of brain death in adults (> 18 years of age) by the American Academy of Neurology was in 2010. In the absence of high-quality evidence, practical (nonevidence based) guidance was provided to clinicians determining brain death. In adults, only one clinical evaluation is required (unless a second exami­ nation is required by statute in some states), ancillary testing is

Issue Theme Brain Death; Guest Editor, Eelco F.M. Wijdicks, MD, PhD

not necessary, and the diagnosis of brain death can be made solely on clinical criteria. Electroencephalography (EEG), cere­ bral angiogram, and nuclear scan are the three preferred ancil­ lary tests, but ancillary tests cannot replace a neurologic examination.2 After their promulgation in 1981, adult brain death guide­ lines were applied only to children older than 5 years as “the brains of infants and young children have increased resis­ tance to damage and may recover substantial functions even after exhibiting unresponsiveness for longer periods com­ pared with adults.”3 Clinical guidelines for the determination of brain death in children were developed by a special taskforce, and first published in 1987.4 These guidelines were revised in 2011 under the auspices of the Society of Critical Care Medicine, the American Academy of Pediatrics,

Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/S-0035-1547540. ISSN 0271-8235.

Pediatric Brain Death Determination

Mathur, Ashwal

and the Child Neurology Society, and provide the minimum standards that must be satisfied before brain death can be declared in infants and children.5 Key updates in the 2011 guidelines included specifications for the initial waiting period before conducting the first brain death examination, who should conduct the examination, number of examina­ tions, interexamination interval, number of apnea tests, PaC02thresholds during apnea testing, and when an ancillary test may be used to reduce the interexamination observation interval or assist with the diagnosis of brain death. A sample checklist was also provided to assist clinicians with consistent performance and documentation of examination elements and ancillary testing. An international expert panel recently published a unifying guideline describing death as “the permanent loss of capacity for consciousness and all brainstem functions.”6 They propose a shift in emphasis during determination of death to the cessation of neurologic or cardiac function, rather than the anatomically based terms such as brain death or cardiac death that continue to be widely used. Although a unifying guideline for determining death may hold merit, its wider acceptance is not yet certain. By general consensus among the medical community and legisla­ tion in the United States, “brain death” is death. To remain consistent with prevailing medical and legal definitions as well as current guidelines, we will continue to use the term brain death in this review.

remained largely stable (~20% of deaths) over the past few decades.9

Epidemiology

Brain death is characterized by coma and apnea with contin­ ued absence of all cortical function as well as brainstem reflexes after exclusion of confounding diagnoses, and after a period of observation to establish irreversibility. Because many underlying conditions can lead to reversible coma in infants and children, the diagnosis of brain death can be established only after careful review of the medical history and performance of detailed neurologic examinations and apnea tests separated by an appropriate interval.

Brain death occurred in 0.9% of all admissions to two pediatric intensive care units (PICUs) in one retrospective study.7 In this study, the most common cause for brain death was trauma, followed by drowning and meningitis. A recent prospective case series studied the mode of death in the PICU at five geographi­ cally diverse teaching hospitals in the United States. Brain death occurred in 16% of 192 patients studied, with withholding or withdrawal of life support the predominant mode of death (in 70%). The length of stay for the vast majority (80%) of patients declared brain dead was less than 7 days, with an overall median of 2.9 days and interquartile range of 1.6 to 6.2 days. As expected in a young and generally healthy segment of the population, these patients tended to have new-onset illnesses or injuries.8 The incidence of brain death determination in the PICU has

Pathogenesis and Pathology Deprivation of oxygen and nutrient delivery to brain tissue is the underlying common pathophysiology irrespective of the proxi­ mate cause leading to brain death. Hypoxic-ischemic brain injury and the resulting edema evolve, and may ultimately progress to brain death after brainstem function completely disappears usually in a rostrocaudal direction (from mesencephalon to medulla oblongata). Severe brain injury may be irreversible at the time of initial presentation, but can only be diagnosed as brain death after a period of observation and complete neuro­ logic examinations. Some major etiologies for severe brain injury and brain death are shown in -Table 1. On autopsy, moderate to severe ischemic changes may be seen throughout the brain. These changes occurred in the cerebral cortex and basal ganglia in 53% to 68%, thalamus in 34%, midbrain 37%, pons 37%, medulla oblongata 40%, and cerebellum in 52% of the cases.10 The lack of uniformity in brain pathology demonstrates that the whole brain death definition used in the United States follows a functional rather than a structural paradigm.

Clinical Presentation

Diagnostic Criteria Prerequisites

Through a careful history, physical examination, and initial diagnostic studies, clinicians should identify an underlying cause for the coma and exclude potentially reversible

Table 1 Etiology of severe brain injury that can lead to brain death 1. Infections: Meningitis, encephalitis 2. Traumatic brain injury: Cerebral contusion, extracerebral or intracerebral hematoma, diffuse axonal injury 3. Intracranial lesions causing elevated intracranial pressure: Intracranial tumor, cyst, abscess, obstructive hydrocephalus 4. Hypoxic-ischemic brain injury: Cardiopulmonary arrest, submersion, cellular hypoxia from carbon monoxide or cyanide poisoning, strangulation, sudden infant death syndrome 5. Vascular events: Massive infarction, hemorrhage from vascular malformations, venous sinus thrombosis, embolism 6. Poisoning: Insecticides, pharmacological agents, lead, alcohols, drugs of abuse 7. Metabolic disorders: Reye syndrome, diabetic ketoacidosis, hepatic encephalopathy, uremia, urea cycle disorders, fa tty acid oxidation disorders, mitochondrial disorders

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diagnoses before brain death evaluation can begin in a deeply comatose infant or child. These investigations may include a blood chemistry profile with glucose, sodium, potassium, blood urea nitrogen, calcium, magnesium, and ammonia stud­ ies to evaluate for an inborn error of metabolism; plasma and urine toxicology screens; drug levels; and EEG. Neuroimaging studies should demonstrate evidence of an acute etiology leading to and consistent with the loss of brain function, although anatomical imaging, such as computed tomography (CT) scan or magnetic resonance imaging (MRI), cannot be used to diagnose brain death. Age-appropriate physiologic parameters should be achieved and maintained before initiat­ ing brain death testing. The initial period of stabilization and diagnostic workup before evaluation for brain death can begin 24 hours or longer following cardiopulmonary resuscitation (CPR) or other etiologies of severe acute brain injury. Normal­ izing body temperature (core temperature > 95°For35°C)and blood pressure, correcting severe metabolic disturbances, and ensuring that sedative or neuromuscular blocking agents have had adequate time to be metabolized are important prereq­ uisites.5 Potentially reversible conditions such as drug intoxi­ cation (e.g., with tricyclic antidepressants, barbiturates, opioids, antiepileptic agents, alcohols, muscle relaxants, bac­ lofen, etc.), locked-in syndrome, Guillain-Barre syndrome, brainstem encephalitis, organophosphate poisoning, and high spinal cord injury can emulate aspects of the brain death examination and should be excluded.11-16 All sedative agents should be discontinued for at least 24 hours in older children and 48 hours in newborns to preclude any interference with the neurologic examination. These periods should be extended to several elimination half-lives after stopping continuous infusions, in the pres­ ence of liver or kidney dysfunction, or after therapeutic hypothermia to ensure adequate metabolism and clearance. Clearance of neuromuscular blocking agents can be estab­ lished by using a nerve stimulator to confirm a sustained “train of four” muscle twitch response. When available, serum levels of sedative or antiepileptic drugs should be in the low- to mid-therapeutic range before conducting a brain death examination.5 Clinical Examination

Brain death criteria in the United States are based on the irreversible cessation of function of the whole brain. The criteria include deep unresponsive coma, loss of all brainstem reflexes (including apnea), and the lack of motor function (excluding spinal reflexes). Examination components and guidelines for their conduct are detailed in - T a b le 2. The first clinical examination can be conducted once the etiology of coma is known, its irreversibility established, and any variables that may confound the physical examination corrected. An observation period of 24 hours between exami­ nations for neonates (37 weeks gestation and up to 30 days age), and 12 hours for infants and children (> 30 days to 18 years of age) is recommended. 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 examination and irre­ Seminars in Neurology

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versible underlying condition. The guidelines also recom­ mend that two different attending physicians perform the neurologic examinations to reduce the chance of diagnostic error, ensure that there are no conflicts of interest, and provide greater certainty in the diagnosis of brain death. The duration of the observation period before the second examination may be reduced if an ancillary study, used in conjunction with the first neurologic examination, supports the diagnosis of brain death. The second neurologic exami­ nation and apnea test (or all components that can be com­ pleted safely) can be performed at any time thereafter to establish brain death.5 Apnea Testing

The 2011 guidelines emphasize that an apnea test be per­ formed with each neurologic examination, to confirm that apnea and coma coexist. The arterial PaC02 should rise at least 20 mm Hg above the baseline and the final value should be > 60 mm Hg with no respiratory effort during the testing period to establish apnea consistent with brain death. The apnea tests can be performed by the same physician who is performing the clinical examination, or by the physician managing the ventilator support for the patient. The patient should be preoxygenated with 100% oxygen before starting the apnea test. Arterial PaC02 should be normalized by adjusting ventilator settings and a baseline blood gas documented prior to initiating apnea testing. During the period of testing, apneic oxygenation can be maintained by providing oxygen flow via an insufflating cannula in the endotracheal tube, on continuous positive airway pressure via the ventilator or by using a Mapleson circuit.17 Tracings on the cardiorespiratory monitor or venti­ lator triggering can occur due to transmitted cardiac pulsa­ tions or a large air leak around the endotracheal tube, thereby creating a false impression of spontaneous breathing. Some ventilators have default apnea settings that provide assisted breaths following a preset time or highly sensitive flow-by trigger mechanisms that automatically trigger a machine breath giving observers the false appearance of a patientinitiated breath.18'19 These default settings potentially create unnecessary confusion and delay in the diagnosis of brain death and also impact resource utilization in busy intensive care units.20 It is therefore very important to expose the patient’s chest and abdomen completely to carefully observe for any respiratory effort during the apnea test, and not rely on ventilator waveforms or bedside monitor tracings alone. An alternative to continuous positive airway pressure therapy (CPAP) for providing apneic oxygenation is a Mapleson circuit. This is a semiclosed circuit that provides fresh oxygen flow close to the circuit’s attachment to the endotracheal tube. It also has an expiratory valve that can be adjusted to provide varying levels of CPAP. With a Mapleson circuit, the patient receives both oxygen flow and CPAP while fully disconnected from the ventilator, thereby obviating false triggering. The clinicians must continually observe the patient for a 5- to 10-minute period after disconnecting the ventilator while maintaining hemodynamic parameters and oxygen satura­ tion. Evidence of any respiratory effort is inconsistent with

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Table 2 Clinical criteria for determination of brain death in infants and children Reversible conditions or conditions that can interfere with the neurologic examination must be excluded prior to brain death testing. 1. Coma. The patient must exhibit complete loss of consciousness, vocalization, and volitional activity. • 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. Loss of all brainstem reflexes including: (a) Midposition or fully dilated pupils that do not respond to light. 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). When uncertainty exists, a magnifying glass should be used. (b) Absence of movement of bulbar musculature including facial and oropharyngeal muscles. 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. (c) Absent gag, cough, sucking, and rooting reflex 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. (d) Absent corneal reflexes 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. Care should be taken not to damage the cornea during testing. (e) Absent oculovestibular reflexes 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 10-50 m Lof ice water. Movement of the eyes should be absent during 1 minute of observation. Both sides are tested, with an interval of several minutes. 3. Apnea. The patient must have the complete absence of documented respiratory effort (if feasible) by formal apnea testing demonstrating a PaC02 > 60 mm Hg and > 20 mm Hg increase above baseline. • Normalization of the pH and PaC02, measured by arterial blood gas analysis, maintenance of core temperature 35°C, normalization of blood pressure appropriate for the age of the child, and correcting for factors that could affect respiratory effort are a prerequisite to testing. • The patient should be preoxygenated using 100% oxygen for 5-10 minutes prior to initiating this test. • Interm ittent mandatory mechanical ventilation should be discontinued once the patient is well oxygenated and a normal PaC02 has been achieved. • The patient’s heart rate, blood pressure, and oxygen saturation should be continuously monitored while observing for spontaneous respiratory effort throughout the entire procedure. • Follow-up blood gases should be obtained to monitor the rise in PaC02 while the patient remains disconnected from mechanical ventilation. • If no respiratory effort is observed from the initiation of the apnea test to the time the measured PaC02 is > 60 mm Hg and 20 mm Hg above the baseline level, the apnea test is consistent with brain death. • The patient should be placed back on mechanical ventilator support and medical management should continue until the second neurologic examination and apnea test confirming brain death is completed. • If oxygen saturations fall below 85%, hemodynamic instability limits completion of apnea testing, or a PaC02 level of 60 mm Hg cannot be achieved, the infant or child should be placed back on ventilator support with appropriate treatment to restore normal oxygen saturations, normocarbia, and hemodynamic parameters. Another attem pt to test for apnea may be performed at a later time or an ancillary study may be pursued to assist with determination of brain death. • Evidence of any respiratory effort is inconsistent with brain death and the apnea test should be terminated. 4. Flaccid tone and absence of spontaneous or induced movements, excluding spinal cord events such as reflex withdrawal or spinal myoclonus. • The patient's extremities should be examined to evaluate tone by passive range of motion, assuming that there are no limitations to performing such an examination (e.g., previous trauma, etc) and the patient observed for any spontaneous or induced movements. ( Continued)

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Table 2

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(Continued)

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

• If abnormal movements are present, clinical assessment to determine whether these are spinal cord reflexes should be done. Source: Reproduced with permission from Nakagawa TA, Ashwai S, Mathur M, Mysore M; Society o f Critical Care Medicine, Section on Critical Care and Section on Neurology of American Academy of Pediatrics; Child Neurology Society. Clinical Report—Guidelines for the Determination of Brain Death in Infants and Children: An Update of the 1987 Task Force Recommendations. Pediatrics 2011;128(3):e720-e740. Copyright 2011 by the AAP.

brain death and the apnea test should be terminated. Carbon dioxide rises by approximately 3 to 5 mm Hg/min, which can be used to determine the timing of follow-up blood gases if apnea continues. The lack of respiratory effort with the PaC02 rising to 60 mm Hg or greater and at least 20 mm Hg above the baseline PaC02 establishes apnea.21-23 If the oxygen saturation falls below 85%, hemodynamic instability occurs, or a PaC02 level of 60 mm Hg cannot be achieved, the patient should be placed back on ventilator support. The apnea test may be attempted again at a later time.5 An ancillary study also can be pursued to assist with the diagnosis of brain death in situations where apnea testing is unsafe or cannot be completed (e.g„ high cervical spine injury, high ventilator settings or oxygen require­ ment). In a retrospective single center review of 228 adults with brain death, an apnea test could not be performed in 7% due to poor baseline hemodynamics or oxygenation and had to be aborted in 3% of patients due to hypoxemia or hypotension.24

Ancillary Tests Under the current guidelines, ancillary tests are not required to make a diagnosis of brain death unless a complete neurologic examination and apnea test cannot be complet­ ed. Ancillary tests are only indicated: (1) when components of the neurologic examination and apnea test cannot be completed; (2) when conditions or confounding variables, such as a medication effect, interfere with the neurologic exam and apnea test; (3) when there are concerns about the validity of the neurologic examination; and (4) to reduce the observation period between examinations.5 The guidelines state that “an ancillary study can be pursued to assist with the diagnosis of brain death in situations where certain examination components cannot be completed.” Key words in this recommendation are “certain examination compo­ nents." In our opinion, using an ancillary test to diagnose brain death when the entire clinical exam in ation (probably including the apnea test) is confounded by medication effect would elevate the ancillary test to a diagnostic test, and is not recommended. If confounders exist, it is reasonable to defer the clinical examination and apnea test for 24 hours or longer as dictated by the clinical judgment of the treating physician. Accepted ancillary tests include demonstration of absence of intracranial circulation on 4-vessel cerebral angiography, radionuclide cerebral blood flow (CBF) study to document Seminars in Neurology

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absence of CBF, and electrocerebral silence (ECS) on EEG.5 Cerebral angiography is used less as it is invasive, technically more difficult in the pediatric population, carries risks asso­ ciated with the contrast material and involves transporting the patient to the angiography suite. Cerebral blood flow and EEG are being used more often as ancillary tests to support the diagnosis of brain death. The American Electroencephalographic Society Guidelines have recommended criteria for brain death recordings.25 The EEG recording should be iso­ electric for a minimum of 30 minutes and show no electrical activity beyond 2 pV at a sensitivity of 2 pV/mm, with filter settings at 0.1 or 0.3 second at 70 Hz. Some experts believe that an EEG may be more specific, although less sensitive, than the radionuclide CBF study. Tc99m hexamethylpropylene-amine oxime (HMPAO) is used at many centers for radionuclide CBF studies because of its brain-specific uptake and ability to adequately visualize the posterior fossa on static imaging.26-28 In clinical practice, a CBF study is being performed more often than an EEG as an ancillary test.29 Under the current guidelines, both an EEG and CBF are acceptable for assisting with brain death determination and have similar confirma­ tory value. However, the sensitivity of ancillary studies in newborns appears to be less than in older children. The diagnostic yield when both an EEG and CBF are initially performed is similar (~70% for either study) in infants and children older than one month of age. For newborns, CBF should be the preferred modality as an EEG with ECS is less sensitive (40%) than absence of CBF (63%) when confirming the diagnosis of brain death.5 If the EEG study shows electrical activity or the radionu­ clide CBF study shows evidence of cerebral flow or cellular uptake, the patient cannot be declared brain dead. The patient should be maintained on ventilator support until death can be declared by clinical examination and apnea testing, or a follow-up ancillary study is performed with results consistent with brain death. There is no specific guidance as to when an EEG should be repeated. A CBF study should only be repeated 24 hours after the first study to allow for adequate clearance of the radiotracer element.30 Clinical Algorithm

A suggested clinical algorithm to assist clinicians in the diagnosis of brain death in infants and children is presented in «-Fig. 1. The time of the second examination confirming brain death (or of the supportive ancillary study if needed) is considered the legal time of death.5

Pediatric Brain Death Determination

C o m a to s e In fa n t o r C hild A. W orkup and trea t potentially reversible causes o f coma B. Stabilize electrolytes, oxygenation/ventilation and hemodynamic status 1 Wait at least 24 hours from IC.U admission befoie first brain death examination

In it ia l B ra in D e a th E x a m in a tio n (b y a n a tte n d in g p h ysician ) P re re q u is ite s : 1. Cause o f coma has been identified and is considered irreversible 2. Core body tem perature is over 95'F (35°C) 3. Systolic blood pressure is w ith in 2 standard deviations o f age-appropriate normal 4. Toxins excluded as contributing fa ctor 5. Sedative/analgesic drug effect excluded as contributing fa ctor 6. M etabolic intoxication excluded as contributing fa ctor 7. Neuromuscular blockade excluded as contributing fa ctor (Do no t proceed w ith the examination unless a ll prerequisites are met) E x a m in a tio n c o m p o n e n ts : A. Coma: Patient unconscious, flaccid, unresponsive to deep painful stim uli (spinal reflexes may persist) B. Absent Brainstem R eflexes/activitv: Pupillary, Corneal, Oculovestibular (Cold caloric), Cough, Gag, sucking and rooting (in infants), no spontaneous respirations C. Apnea: No spontaneous respirations in presence o f pC02 challenge to > 60 mm Hg and 20 m m Hg above baseline value. (If any response is present under sections A, B o r C, th e patient is NOT brain-dead. Continue observation and repeat the examination after 24 hours or later)

W ere a ll e x a m in a tio n c o m p o n e n ts (A -C ) a b le to be c o m p le te d ?

J

NO

A n c illa ry s tu d y (EEG, CBF o r c e re b ra l

C o n tin u e O b s e rv a tio n a w a itin g

a n g io g ra m ) s u p p o r ts b r a in d e a th ?

c o n fir m a to r y e x a m YES

I

1[«□ The p atient is NOT brain-dead. Continue observation and repeat the initial examination an d/ or ancillary test after 24 hours or more

C o n firm a to r y b ra in d e a th e x a m in a tio n a n d a p n e a te s t (b y a sec o n d a tte n d in g p h y s ic ia n ) c o n d u c te d a f te r an a g e d e p e n d e n t in te r -e x a m in a tio n in te r v a l (Review and reconfirm th a t the prerequisites fo r examination are fulfilled) A. Newborns 37 weeks gestation to 30 days: Examinations 24 hours apart remain unchanged w ith persistence o f coma, absent brainstem reflexes and apnea. B. 31 days to 18 years: Examinations 12 hours apart remain unchanged w ith persistence o f coma, absent brainstem reflexes and apnea. Note: If any examination component or apnea test cannot be completed during the second examination, an ancillary study is again required to confirm brain death S e c o n d e x a m in a tio n ± s u p p o rtiv e a n c illa ry s tu d y ( if ne ed ed ) c o m p le te d , a n d c o n fir m s b ra in d e a th ?

J

YES

THE PATIENT IS BRAIN DEAD TIME OF DEATH: The tim e o f the second brain death exam ination or th e ancillary study needed to support the second examination. END OF LIFE CARE: The physician should inform the fa m ily o f th e death using concrete terms, and alert the local organ procurem ent organization to discuss organ donation w ith next o f kin. Medical examiner notification and autopsy consent as needed.

NO, evidence o f brain viab ility is observed The p atient is NOT brain-dead. Continue observation and repeat examination a n d/ or ancillary test after 24 hours o r more. If signs indicating some brain viability persist, options fo r continued care vs. withdrawal o f life support may be discussed w ith the family

Note: Ancillary studies (EEG & CBF) are n o t required for any age group but can be used when (i) components of th e examination or apnea testing cannot be safely completed; (ii) there is uncertainty about th e examination; (iii) if a medication effect may interfere w ith evaluation or (iv) to reduce the observation period betw een the first and second examinations._________

Fig. 1 Clinical algorithm for the diagnosis of brain death in infants and children. ICU, intensive care unit; EEG, electroencephalogram; CBF, cerebrospinal fluid. (Adapted from and reproduced with permission from Nakagawa TA, Ashwal S, Mathur M, Mysore M; Society of Critical Care Medicine, Section on Critical Care and Section on Neurology of American Academy of Pediatrics; Child Neurology Society. Clinical Report—Guidelines for the Determination of Brain Death in Infants and Children: An Update of the 1987 Task Force Recommendations. Pediatrics 2011 ;128(3):e720-e740. Copyright 2011 by the AAP.)

Comparing Current Pediatric and Adult Brain Death Guidelines Current guidelines for determining brain death in adults and children have many similarities, but also some differences.2,5 Both emphasize prerequisites that must be fulfilled before starting the clinical evaluation for brain death, including

Mathur, Ashwal

establishing a proximate cause for coma, ensuring clearance of sedative and neuromuscular blocking agents, correction of severe electrolyte, acid-base and endocrine disturbances, and maintaining a normal blood pressure. The body temperature should be maintained over 36°C in adults and 35°C in children. Both guidelines emphasize the importance and primacy of clinical examination over ancillary testing. Both stipulate that ancillary tests can be used when uncertainty exists about the reliability of parts of the neurologic exami­ nation or when the apnea test cannot be performed. Under both guidelines, ancillary tests may be used to shorten the duration of the “observation period”; however, in the adult guidelines this refers to the period before the single exami­ nation required, and in the pediatric guidelines to the inter­ examination interval between neurologic assessments. The blood gas criteria in adults that support the diagnosis of brain death are arterial PC02 is > 60 mm Hg (or 20 mm Hg in­ crease in arterial PC02 over a baseline normal arterial PC02). The pediatric criteria require that the arterial PaC02 be both 20 mm Hg above the baseline and > 60 mm Hg. This would provide further clarity in situations such as chronic lung disease where the baseline PaC02 is above normal. One key difference between the guidelines is the need for two examinations and apnea tests in children versus one in adults, with the stipulation that several hours should have passed since the brain insult to preclude the possibility of recovery. Although there are no reports of children recovering neurologic function after meeting brain death criteria based on neurologic examination findings, the recommendation for two examinations was based on guideline committee con­ sensus. This recommendation has been criticized for making the diagnosis of brain death in children unnecessarily com­ plicated, with a delayed diagnosis potentially affecting organ donation.32The committee’s opinion was that two separate examinations by different physicians reduce the chance of diagnostic error, ensure that there are no conflicts of interest, and provide greater certainty in the diagnosis of brain death. Due to its implications, a committed diagnosis of brain death should necessarily require a higher standard than other less crucial medical diagnoses. Cases with “improvement” and apparently reversible brain death days after brain injury have diagnostic errors, when re-examined critically.33 What if this and other such patients mistakenly diagnosed as brain dead after the first examination had been taken off life support? By continuing the requirement for two examinations, the com­ mittee intentionally sought to eliminate the chance that a single clinician, even if well qualified and good intentioned, could diagnose brain death in error. An inter-examination observation period of 24 hours for term newborns (37 weeks gestational age) to 30 days of age, and 12 hours for infants and children (over 30 days to 18 years) is recommended. These intervals are again consensusbased with a longer, more cautious observation period for newborns. The pediatric guidelines state that the examinations should be performed by different attending physicians “qual­ ified and competent to perform the brain death examination.” The guidelines require that experienced clinicians who are Seminars in Neurology

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familiar with neonates, infants and children and have specific training in neurocritical care perform the examination. The amount of experience and training required is not specified. Qualified clinicians include pediatric intensivists and neonatologists, pediatric neurologists and neurosurgeons, pedi­ atric trauma surgeons, and pediatric anesthesiologists with critical care training. Adult specialists should have appropri­ ate neurologic and critical care training to diagnose brain death when caring for the pediatric patient from birth to 18 years of age. In practice, most examinations are being performed by pediatric intensivists and pediatric neurolo­ gists or neurosurgeons.29 Some institutions such as ours further require that at least one of the examinations be performed by a neurologist or neurosurgeon. The adult guidelines allow that “it seems reasonable to require that all physicians making a determination of brain death be intimately familiar with brain death criteria and have dem­ onstrated competence in this complex examination,” but do not specify further who the physician should be or how competence should be determined. Both adult and pediatric guidelines include a checklist to help to ensure that all components of the examination, and ancillary studies if needed, are completed and documented appropriately. Under the pediatric guidelines, the time of the second neurologic examination is the time of death. The clinical algorithm is shown in ►Fig. 1.

evaluation of adult patients for brain death. Understanding of brain death improved significantly without adversely impacting psychological well-being in those present 30 and 90 days after the intervention. Allowing families to be present throughout the brain death evaluation may promote understanding and accep­ tance of brain death.39There is a national trend toward allowing family presence during procedures and even CPR in critically ill children.40 Whether being present during brain death testing would also improve acceptance among the parents/guardians of a child should be the subject of future studies. Diagnosing Brain Death on Extracorporeal Membrane Oxygenation

Clinical suspicion for brain death may arise in a patient supported by extracorporeal membrane oxygenation (ECMO) if the mixed venous oxygen saturation is high, indicating a drop in oxygen consumption. Although the core temperature and hemodynamics are easily controlled by ECMO so that a reliable clinical examination can be performed, a conventional apnea test may not result in a sufficient increase in PaC02 off the ventilator as C02 clearance by the oxygenator membrane is highly efficient. The sweep gas flow should be lowered and adjusted (0.1 L/min-0.5 L/min) while the rise in C02 is continuously monitored through an in-line sensor in the ECMO circuit41 Anencephaly and Brain Death

Pitfalls, Emerging Issues, and Controversies Therapeutic Hypothermia

Therapeutic hypothermia after cardiac arrest has become the standard of care in adults and newborns, and two large National Heart Lung and Blood Institute Health sponsored trials comparing therapeutic normothermia to therapeutic hypothermia in pediatric patients after in-hospital and outof-hospital cardiac arrest are nearing completion.34 Hypo­ thermia depresses central nervous system function, and delays drug metabolism. Achieving a normal temperature before clinical brain death examination is necessary, but by itself may not be sufficient to eliminate confounding findings due to delays in metabolism of sedatives and analgesics. This can be a confounding variable while conducting brain death testing.35 The development of new assays for screening and quantification of medications in plasma may assist the clini­ cian in excluding such confounding variables. A multianalyte procedure using ultra-high performance liquid chromatogra­ phy with tandem-mass spectrometric detection can simulta­ neously screen and quantify over 90 central nervous system­ suppressing drugs.36 Family Presence during Brain Death Determination

Brain death remains a difficult concept to understand for medi­ cal professionals and lay persons alike. Without the acceptance that their loved one has died, although vital signs are being maintained through modern technology, families cannot shift their focus toward making end-of-life decisions such as an autopsy or organ and tissue donation.37,38 A recent randomized control trial assessed the impact of family presence during Seminars in Neurology

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Anencephaly is a neural tube defect in which the infant is born without a cerebrum, though some may have a rudi­ mentary brainstem. Anencephalic infants lack conscious­ ness and in the natural course are either stillborn or die shortly after birth. Ashwal and colleagues serially exam­ ined 12 live-born anencephalic infants to determine if they would meet clinical criteria for whole-brain death within a 7-day period.42,43 Intensive care was provided at birth in half the patients, and only when death was imminent in the others. Most infants exhibited various combinations of brainstem reflexes. Ophthalmologic and otologic develop­ mental abnormalities confounded the clinical examination of cranial nerve function in some. Organ function could be maintained in those provided intensive care from birth; however, only two infants (16.7%) ultimately met clinical criteria for brain death. Neuropathological findings indi­ cated that no infant had a normally formed cerebrum. Brainstem neuronal activity may have accounted for motor responses in some patients, but even at this level neurons were scanty or absent. Thus, anencephalic infants frequent­ ly do not meet clinical criteria for brain death, and ancillary studies such as EEG and CBF are inappropriate because there are no cerebral hemispheres. Therefore, these infants cannot be considered for organ donation after brain death. If a woman chooses to carry an anencephalic fetus to term and desires to donate the baby’s organs, donation after circulatory determination of death may be an option if the parents agree to provision of life-support at birth. Surgical transplant teams can then be mobilized, followed by elec­ tive withdrawal of life support and organ procurement after death.

Pediatric Brain Death Determination

Conclusion The determination of brain death in infants and children involves the identification of a cause for irreversible acute brain insult, exclusion of confounding conditions, and con­ tinued absence of all cortical function as well as brainstem reflexes as determined on two clinical examinations and apnea tests. The time of the second examination confirming brain death (or of a supportive ancillary study if needed) is considered the legal time of death.5

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