Journal of Perinatology (2007) 27, S59S62 r 2007 Nature Publishing Group All rights reserved.

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ORIGINAL ARTICLE

Brain death in the newborn

KC Sekar
OU Medical Center, Childrens Hospital, Everett Drive, Oklahoma City, OK, USA (1740 to 1850) and recent history after 1840.4 The history of death is interesting as there was struggle to dene what constituted Life. There was confusion whether stopping of the heart beat or respiration dened death. Religious beliefs and cultural practices added to this confusion. There was also fear of wrongfully pronouncing someone dead. In the modern era, the requirement to dene brain death became important when transplantation of organs started to occur between living donors. The major milestone in this regard was the rst heart transplantation by Dr. Christian Barnard in 1967, when the heart of a brain-dead donor was transplanted in another person. In 1968, the Harvard criteria for brain death was published, which consisted of coma, apnea, lack of spontaneous movement, absence of reexes, isoelectric EEG, and no evidence of pharmacological depression for 24 hours.5 Since then, several variations of these criteria have been published.6,7 These criteria applied mostly to adults and there was debate whether they applied to children and infants. In 1981, the US presidential commission excluded children less than ve years of age from the Harvard criteria published for adults.8 However, at that time, there was no precise biological evidence available for this age cut-off. In England, brainstem death was equated to brain death, which could be assessed without the need for an EEG.9 Subsequently, cerebral perfusion studies and EEGs were proposed as useful bedside tools to assist in conrming brain death.3,10,11 In 1987, an ad hoc task force committee representing the American Academy of Pediatrics, American Academy of Neurology, American bar Association, American Neurological Association, Child Neurology Society and the National Institute of Neurological and Communication Disorders and Stroke published guidelines for the determination of brain death (Table 1).12 These guidelines included history, physical examination, neurodiagnostic studies and age-related observational periods of up to two months, two months to one year, and over one year of age. In children, over one year of age, laboratory testing was optional. These guidelines excluded preterm infants and term infants less than seven days of age. Subsequently, data on brain-dead newborns have been published.13 The exact incidence of brain death in newborns is unknown, but earlier reports estimate incidence at about 400 per year.14 However, later reports from Loma Linda and others estimated brain death to be 2.97% of total newborn deaths. On the basis of these reports, the incidence of brain death in newborns would be

Brain death in the newborn is usually determined by neurological examination, apnea testing and a duration of observation period. In addition, other conrmatory studies such as electroencephalogram and cerebral blood ow are performed to determine the cause of coma. These conrmatory studies are unreliable in the newborn and are helpful only to shorten the duration of observation period if positive. The American Academy of pediatrics ad hoc task force guidelines for the determination of brain death in children did not include preterm infants and term infants less than seven days of age due to lack of available data in this age group. Recent data from organ sharing network suggest that these guidelines could be used in infants less than seven days of age. Journal of Perinatology (2007) 27, S59S62. doi:10.1038/sj.jp.7211718

Keywords: apnea test; brain death; cerebral blood ow; electroencephalogram; neurological examination; newborn

Introduction Death is dened as an irreversible cessation of all vital functions, especially as indicated by permanent stoppage of the heart, respiration and brain activity: the end of life. Brain death is dened as the nal cessation of activity of the central nervous system, especially as indicated by a at electroencephalogram (EEG) for a predetermined length of time.1 The Uniform Determination of Death Act denes death as: (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain. A determination must be made in accordance with accepted medical standards.2 Unfortunately, the accepted medical standards that apply for adults, such as EEG and cerebral blood ow (CBF) measurements, are not reliable in newborns because of the open fontanel and lack of increase in intracranial pressures as seen in adults. Therefore, it has been suggested that in newborns, we may need to consider brainstem death rather than brain death3 in the evaluation of coma. A brief review of the literature on brain death in the newborn is described below. Historical aspects and incidence There are three distinct periods described in history about death; the ancient period dating before 1740, the period of Enlightenment
Correspondence: Professor KC Sekar, OU Medical Center, Childrens Hospital, 1200 N Everett Drive, Oklahoma City, OK 73104, USA

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Table 1 Ad Hoc Task Force guidelines for determination of brain death in children
A. History: Determine the cause of coma to eliminate any reversible conditions B. Physical examination criteria: 1. Coma and apnea 2. Absence of brain stem function a. Mid position or fully dilated pupils b. Absence of spontaneous oculocephalic (also called the dolls eye reex) and caloric-induced eye movements c. Absence of movement of bulbar musculature, corneal, gag, cough, sucking and rooting reexes d. Absence of respiratory effort with standardized testing for apnea 3. Patient must not be hypothermic or hypotensive 4. Flaccid tone and absence of spontaneous or induced movements, excluding activity mediated at spinal cord level 5. Examination for brain death should remain consistent throughout the predetermined period of observation C. Observation period according to age: 1. Seven days to two months: two examinations and EEGs 48 hour apart 2. Two months to one year: two examinations and EEGs 24 hour apart, or one examination and an initial EEG showing ECS, combined with a radionuclide angiogram showing no CBF; or both 3. More than one year: two examinations 1224 hours apart; EEG and isotope angiography optional
Abbreviations: CBF, cerebral blood ow; ECS, electrocerebral silence; EEG, electroencephalogram. Reproduced with permission from Pediatrics, Vol 80, Page(s) 298300, Copyrightr 1987, by the AAP.

approximately 550 per year.3 The causes of brain death in the newborn are hypoxic ischemic encephalopathy (61%), massive intracranial hemorrhage due to birth trauma (8%), congenital malformation (6%), central nervous system vascular injury (6%), meningitis/infection (7%), nonaccidental trauma (4%), sudden infant death syndrome (7%) and metabolic disease (1%).3 Tests for brain death in newborns Neurological examination A careful neurological examination should be performed to document complete lack of responsiveness rather than subtle conscious behaviors. Assessment of brainstem function and absence of brainstem reexes should be documented. Brain-stem reexes are generally present in infants by 32 weeks gestational age. Assessment of papillary reactivity and ocular motility may be difcult in a compromised infant on ventilator support. Assessing caloric response is difcult in newborns owing to their small external ear canal. Therefore, oculocephalic (Dolls eye) reex and oculovestibular (Caloric) reex should both be examined. Corneal reex is easy to examine in neonates and its presence indicates intact brain-stem function. However, it is the least reliable test. Assessment of auditory function is difcult in a comatose infant, but if necessary a brainstem auditory evoked response test should be obtained. Assessment of the lower cranial nerve is limited to assessment of the gag reex. While performing neurological examination, it is essential to ensure that the examination is not compromised by pharmacologic effects of anticonvulsants such as phenobarbital or other sedatives.3,13 Apnea testing Apnea testing is the most critical test in diagnosing brain death in the newborn. It is performed after allowing sufcient
Journal of Perinatology

time for CO2 to increase while providing adequate oxygenation; ideally, this should be accomplished without adverse cardiovascular effects.8 Typically, oxygen should be preadministered for 10 minutes while the infant is on the ventilator, then the ventilator should be discontinued allowing the CO2 to rise. Oxygen supplementation should be continued while the infant is weaned from the ventilator. The threshold for CO2 is 60 torr for newborn infants. At this point, there should be a lack of sustained respiratory effort. Few ineffectual respiratory efforts should not be considered reversible brain defect.15,16 Carbon dioxide accumulates slowly in brain dead infants owing to lack of production of CO2 by the brain.16,17 Generally, this test should take ve to 15 min to reach the CO2 threshold of 60 torr. It is important to note that compressive brain-stem lesions may mimic brain-stem death, which could be seen in newborns with posterior fosa subdural hematomas, Dandy Walker syndrome or ArnoldChiari malformation and brain tumors.3,18,19 Apnea testing can be successfully performed in all infants greater than 32 weeks gestational age. Duration of the observation period The task force recommendations did not include infants less than seven days of age owing to the lack of data and unreliability of diagnostic studies. Ashwal3 pooled data, from their center and others, of those patients primarily referred for transplantation. They also included infants who were in a coma and had conrmed brain death in this study. They found that the time to transplantation was 2.8 days in infants less than seven days and 5.2 days in infants greater than seven days.3,14,20 On the basis of their observation, they suggested that the average duration to conrm brain death in infants less than seven days would be 24 to 48 hours.

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Diagnostic studies The diagnostic studies commonly performed are electroencephalogram (EEG) and cerebral blood ow (CBF) studies. Electroencephalogram Electrocerebral silence (ECS) is conrmatory evidence of brain death. This is usually seen as a at line in EEG tracing. There are no EEG recommendations for infants less than seven days of age. The American Electroencephalographic Society has published guidelines for conrming brain death.21 However, there are technical difculties in small infants to fulll these criteria, such as shorter inter-electrode distance, machine sensitivity, photic stimulation, external artifacts in the ICU, and many other difculties, making the interpretation of EEG difcult. Medications given to infants such as phenobarbital may also interfere with recordings. However, it has been shown that therapeutic levels of phenobarbital (15 to 40 mg/ml) do not affect the EEG.22 If the infant is brain dead, the EEG showing ECS is between 51 and 100%.23 If the EEG shows ECS, no further EEG is necessary. If the rst EEG shows activity, 64% of the second EEG will show ECS. In the remaining infants (36%), a 48 hours observation period is recommended. If the clinical exam is unchanged brain death can be conrmed.3 The task force did not recommend EEGs in children over one year of age. There have been reports of EEG activity returning in brain-dead infants; however, none of these infants recovered. Ashwal and Serna-Fonseca24 report that the return of EEG activity in brain-dead infants is overemphasized. Cerebral blood ow studies Newborn infants have open fontanel and, therefore, the increase in intracranial pressure seen after acute injury in older children is not present. Therefore, the perfusion pressure in newborns may not decrease despite low mean arterial pressure. Thus, CBF may be present in brain-dead newborns, making this test somewhat unreliable. There are various methods available to measure CBF, which are cerebral angiography, transcutaneous Doppler sonography, computed tomography with injection of contrast material or Xenon, digital subtraction angiography, positron emission tomography, and single-photon emission computed tomography.3,24 Among these, the most commonly used technique has been radioisotope scanning and Doppler CBF velocity. However, the CBF and EEG correlation has been very poor. Ashwal and Schneider13 compared CBF and EEG in 30 brain-dead neonates. Of the 19 infants, without CBF, eight (42%) had ECS and 11 (58%) had EEG activity. In the same series of the 11 infants with CBF, four (36%) had ECS and seven (64%) did not. This observation emphasizes the limitations of CBF in determining brain death in newborns. Doppler CBF measures the progression of velocity changes in brain-dead neonates. These changes include the loss of diastolic blood ow, the appearance of retrograde diastolic blood ow, decrease in systolic blood ow in the anterior cerebral artery with

unchanged ow in the common carotid artery, and nally no ow in all the cerebral vessels.25 Digital subtraction angiography is another technique used to measure blood ow.26 Limited data exist to use these methods in routine practice to determine brain death. Assessment of brain metabolic activity using spectroscopy has also been described in brain-dead neonates.3 Ashwal and Schneider,13 in a retrospective review of 18 preterm and term infants less than one month of age with conrmed brain death based on coma, apnea with inability to sustain respiration and absent brain stem reexes, analyzed their clinical course and reported the following observation.1 Neurodiagnostic tests, such as EEG and radionuclide scanning, reconrmed clinically determined brain death in only one-half to one-third of the patients.2 ECS conrmed brain death, if clinical ndings remained unchanged in the absence of barbiturates, hypothermia or cerebral malformations during a 24-h period.3 Absence of radionuclide uptake associated with initial electrocerebral silence was correlated with brain death.4 Term infants clinically brain dead for two days and preterm infants brain dead for three days did not survive despite EEG or CBF status.5 Phenobarbital levels >25mg/ml suppress electroencephalographic activity in these infants. These ndings suggest that determination of brain death in the newborn can be made solely by using clinical criteria. Supplemental diagnostic studies are of potential value to shorten the period of observation.

Conclusion Determination of brain death in the newborn requires repeated clinical examination with particular attention given to determine
Table 2 Clinical and diagnostic criteria to pronounce brain death
Clinical exam Apnea test EEG + + ECS Absent Present Not available + + EEG ? Repeat EEG Absent ECS Present Not available EEG ? Repeat EEG Absent EEG ? Present Not available Exam + EEG k Death Exam + EEG + Observation k Death Cerebral blood ow Conrmation Death

? Repeat +

Abbreviations: +, positive examination; ?, Uncertain results; ECS, electrocerebral silence; EEG eclectroencephalogram. Journal of Perinatology

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the cause of coma. Neurological examination is also pertinent, particularly with regard to brain-stem reexes. Apnea testing should be performed as described earlier. EEG and CBF studies may not show abnormalities that are described in older patients. An observation period of 24 to 48 hours is recommended. If the EEG is isoelectric or if CBF is absent, the observational period can be shortened. However, this observational period may have to be extended in situations where the determination of the cause of coma or brain-stem reexes is uncertain. A summary of clinical examination and diagnostic tests used to determine brain death is shown in Table 2. The task force guidelines did not include infants less than seven days of age in determining brain death in children. Recently, Ashwal and Serna-Fonseca24 published a modied brain death criteria based on the 1987 task force recommendations, which includes newborns less than seven days of age. The American Academy of Pediatrics should revisit these recommendations and consider including this age group in the guidelines for the determination of brain death in children. Consideration should also be given to religious, cultural, legal and ethical issues when determining brain death in the newborn. Finally, excellent reviews on brain death in newborns have been published by Ashwal et al.3,13,24 and commented on by Volpe.27 References
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