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EEG guidelines in the diagnosis of brain death
Neurophysiologie Clinique/Clinical Neurophysiology (2015) 45, 97—104
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REVIEW/MISE AU POINT
EEG guidelines in the diagnosis of brain death L’EEG dans le diagnostic de mort cérébrale W. Szurhaj a,b,∗, M.-D. Lamblin a, A. Kaminska c, H. Sediri a a
Service de neurophysiologie clinique, CHRU, 59037 Lille cedex, France Faculté de médecine, Université Lille 2, Lille, France c Laboratoire de neurophysiologie clinique, Hôpital Necker—Enfants Malades, AP—HP, Paris, France b
Received 5 November 2014; accepted 9 November 2014 Available online 14 January 2015
KEYWORDS Electroencephalography; EEG; Brain death; Recommendations; Technical aspects
MOTS CLÉS Électroencéphalogramme ; EEG ;
∗
Summary In France, for the determination and diagnostic validation of brain death the law requires either two EEG recordings separated by a 4-hour observation period, both showing electrocerebral inactivity; or cerebral angiography examination. Since EEG is available in most hospitals and clinics, it is often used in this indication, at the patient’s bedside, especially in the context of organ donation. However, very precise methodology must be followed. The last French guidelines date back to 1989, before the development of digital EEG recording. We present the new guidelines from the Société de Neurophysiologie Clinique de Langue Franc ¸aise. Electrocerebral inactivity may be confirmed when a 30-minute good quality EEG recording shows complete electrocerebral silence, defined as no cerebral activity greater than 2 uV, having first ruled out the possible influence of sedative drugs, metabolic disorders or hypothermia. In the presence of sedative drugs, CT brain angiography will be the gold standard test for this diagnosis. In the newborn, the utmost caution is indicated since electrocerebral inactivity can be observed in the absence of cerebral death. In the infant, the criterion for the observation period to be respected between both EEG recordings needs to be more clearly refined. © 2015 Elsevier Masson SAS. All rights reserved.
Résumé En France, la loi exige que le diagnostic clinique de mort cérébrale soit confirmé par deux EEG inactifs réalisés à 4 heures d’intervalle ou une angiographie cérébrale. La disponibilité de l’EEG dans la plupart des centres hospitaliers et sa facilité de réalisation au lit du patient en font toujours un examen très utilisé dans cette indication, notamment dans le cadre des prélèvements d’organes. Sa réalisation exige toutefois une méthodologie
Corresponding author. Service de neurophysiologie clinique, CHRU, 59037 Lille cedex, France. Tel.: +33 06 76 76 32 07. E-mail address: [email protected] (W. Szurhaj).
http://dx.doi.org/10.1016/j.neucli.2014.11.005 0987-7053/© 2015 Elsevier Masson SAS. All rights reserved.
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W. Szurhaj et al.
Mort cérébrale ; Recommandations ; Aspects techniques
précise. Les dernières recommandations franc ¸aises dataient de 1989, avant l’avènement de l’EEG numérisé. Nous présentons ici les nouvelles recommandations de la Société de neurophysiologie clinique de langue franc ¸aise. L’EEG sera considéré « inactif » lorsqu’un tracé de 30 minutes, de bonne qualité, montre un silence électrique, défini comme l’absence d’activité cérébrale d’une amplitude supérieure à 2 V, à la condition d’exclure l’influence possible de la sédation, de troubles métaboliques et d’une hypothermie. En cas d’imprégnation par des substances sédatives, l’angioscanner sera préféré. En contexte néo-natal, une grande prudence est nécessaire, un tracé inactif pouvant être observé en l’absence de mort encéphalique. Chez le nourrisson, les critères d’intervalle entre les deux EEG devront encore être mieux définis. © 2015 Elsevier Masson SAS. Tous droits réservés.
Abbreviations
CT ECG EEG
computed tomography electrocardiogram electroencephalogram
Summary of guidelines It is mandatory for the physician interpreting EEG in the context of brain death to obtain the maximum amount of data: • before performing an EEG, essential clinical data must be collected: patient’s last name, first name and date of birth, circumstances and origin of the coma, especially date and time of the presumed onset of the coma, and imaging results; • the clinical examination (neurologic assessment) must specify brain death criteria (deep coma; absence of spontaneous respiration; absence of brainstem reflexes); • any clinical suspicion of pharmacological, biochemical or toxic factors, as well as metabolic disturbance or hypothermia should be mentioned in the evaluation report; • data regarding the EEG recording should include: date, time and location of the EEG recording and possibly scalp condition. Drugs administered in the preceding 24 hours or drugs screened for in blood and urine should be indicated, as well as body temperature and hemodynamic parameters, especially mean arterial pressure, which should be maintained above 50 mmHg. The execution parameters must be rigorously observed: • the recording should be performed by a specialized technician, or physician who is board-certified in electroencephalography, these being the only persons qualified to identify and reject artifacts, implement the required polygraphy set-up, perform necessary activation procedures and document all relevant data on the recording;
• EEG recording should include a minimum of eight scalp electrodes (standard ones or ideally needle electrodes): FP2, C4, O2, T4, FP1, C3, O1, T3. Cz is recommended; • simultaneous ECG (in D1) and respiratory movement recording can help identify certain activities as artifacts. It seems essential to be able to have these two recordings during the entire EEG duration; • impedances for each electrode must be between 100 and 10,000 . The recording will be performed at a sampling rate of at least 256 Hz, and the high-pass filter should be set at 0.53 Hz. Digital filters below 70 Hz should not be used (apart from the notch filter at 50 Hz), as this could attenuate high-frequency brain waves; • the EEG tracing should include at least 30 minutes of good quality recording in order to be properly interpreted; • auditory and bilateral somatosensory stimuli (touch and pain) should be repeatedly performed, and be clearly indicated on the recording (for somatosensory stimuli, indication of the stimulated point and excluding electrostatic shocks); • the technician must note on the recording all events that occur during the examination; • system calibration is usually automated in digital EEG; however the integrity of the entire recording system should be tested by voluntarily creating artifacts (shaking the connecting leads of the electrodes for example); • in order to validate the lack of electrical activity on the EEG, we recommend maintaining the patient’s body temperature above 34 ◦ C (minimum recommended). In the case of hypothermia, with a temperature below 34 ◦ C, the patient’s body will need to be warmed up before proceeding with the EEG; • we recommend that the EEG be performed at least 12 hours after cardiorespiratory arrest; • it is necessary to repeat the EEG with a minimum of 4 hours between the two examinations (minimum of 4 hours calculated from the beginning of each recording); • since techniques based on the study of intracerebral blood flow (cerebral angiography) are not influenced by sedative medications, we recommend using these techniques rather than EEG in this situation; • if it is impossible to use these alternative techniques, the EEG interpretation must take into account the sedative drugs previously administered, and eventually residual drug levels in the blood sample.
EEG guidelines in the diagnosis of brain death The interpretation conditions should allow for the best interpretation possible, without any possible objections: • electrocerebral inactivity (term of reference rather than using ‘‘flat-lined’’, ‘‘null’’, ‘‘isoelectric’’) is defined by the absence of cerebral activity above 2 V amplitude, even when auditory and nociceptive stimuli are performed in a bilateral manner; • the interpretation of the EEG will be easier on a good quality display screen with a minimum resolution of 1280 × 1024. The optimal screen size for proper reading is 17 inches or more; • for an optimal interpretation of the recording, the reading settings should range between 3 and 5 v/mm (inclusive) with a speed of 20 s per display screen/page (i.e. 15 mm/s). A 30 mm/s speed (10 s per display screen) can be used to better appreciate the signal; • for paper traces, the printer should have a minimum resolution of 300 DPI; • the interpretation should be carried out using long distance montages, without filters; • the interpretation report can only be written by a physician specialized in functional exploration of the central nervous system. EEG results should only be communicated to physicians qualified to confirm a diagnosis of brain death, and no one else. In children, due to brain immaturity, specific recommendations should be taken into account: • the clinical examination and precise brain death criteria should be detailed on the EEG request and be repeated; • in premature babies and newborns under 7 days of life, because of brain immaturity, EEG is not a reliable indicator of brain death and cerebral angiography should be used; • between the age of 7 days and 1 month, it is recommended to perform two EEGs separated by a 48-hour interval and above all to take into account clinical criteria; • beyond the age of 1 month and up to 1 year, the recommended interval between the two EEGs is 24 hours; • beyond the age of 1 year, the recommended delay between two examinations is similar to that applied to adults (i.e. 4 hours); • under the age of 2 months, the interpreting physician must be experienced in performing EEG in newborns and infants.
99 both cerebral perfusion scintigraphy confirming irreversible cerebral insult and EEG showing electrocerebral inactivity are mandatory for the diagnosis of brain death. In Australia and in some Asian countries, clinical criteria based on the absence of brainstem reflexes are applied. In summary, the major differences between criteria listed in the different guidelines [27] are: the number of examining physicians required to confirm brain death, their seniority and level of experience; additional examinations are sometimes mandatory and sometimes only recommended; the duration of the observation period after declaration of brain death varies, the most usual being around 24 hours; the apnea test is the object of controversy because of potentially noxious consequences on internal organs [23]. Some countries, in which organ transplantation is not performed (some African countries for example), do not have brain death criteria.
French laws In France, the last regulatory text still in application today was published in 1996. It governs the procedures and necessary conditions for the diagnosis of brain death and also organ donation. Decree no 96-1041 of December 2, 1996 relative to the diagnosis of death, prior to removing organs, tissues or cells for therapeutic or scientific purposes and modifying the Public Health Code. Section 3. —– Removing organs from a deceased patient. Sub-section 1. —– Validation of brain death before removing organs for therapeutic or scientific purposes. Art. R. 671-7-1. —– If the person is in cardiac and respiratory arrest, brain death can only be validated if the three following clinical criteria are simultaneously observed: • lack of any evidence of consciousness and of spontaneous motor activity; • absence of all brainstem reflexes; • total absence of spontaneous respiration. Art. R. 671-7-2. —– If the person, whose death was clinically validated, is assisted via mechanical ventilation and conserves hemodynamic functions, the absence of spontaneous breathing is verified using the hypercapnia test. Furthermore, in addition to the three clinical criteria mentioned in the article R. 671-7-1, the following tests are mandatory to validate the irreversible nature of the brain insult:
Full-length guidelines The utility of EEG in the diagnosis of brain death is regarded differently in different countries. In the United States, EEG is recommended but is not mandatory [16,25,26]. In Canada, EEG is no longer recommended for this indication. In Europe, an EEG laboratory test to validate the diagnosis of brain death is not recommended in all countries. In several countries, the apnea test is performed, to look for hypercapnia based on an increase of PCO2 > 20 mmHg compared to normal. The duration of the observation period between the initial event and the EEG varies from 0 to 48 hours, especially when anoxia is the cause of brain death. In Japan,
• either two electroencephalogram recordings showing electrocerebral inactivity, respecting a 4-hour observation period between both tests, conducted with maximal amplification on a 30-minute recording; the result must be immediately recorded by the physician who interpreted the recording; • or cerebral arteriography showing lack of blood flow to the brain; the radiologist who interpreted the imaging exam must immediately record the result. Art. R. 671-7-3.-III. —– When brain death has been validated for a person undergoing mechanical ventilation
100 retaining hemodynamic functions, the brain death report indicates the results of the concordant clinical observations of two physicians adhering to the conditions mentioned in article L. 671-10. Furthermore, it mentions the result of examinations as defined in the 1st or 2nd addendum of article R. 671-7-2, as well as the date and time of the report. The report is signed by the two physicians mentioned above. The EEG in this last text appears as one of the mandatory examinations, along with cerebral arteriography (or more recently cerebral CT-angiography), necessary to confirm the irreversible and definite nature of the brain destruction. Specific conditions of duration, amplification and observation period between the examinations are clearly defined, but refer to traditional EEG paper recordings.
Advantages and limits of EEG in the early diagnosis of brain death The main advantage of EEG is its non-invasive, reproducible nature, and it is easily available in most hospitals. In a study conducted in France in 1997, C. Fischer [9] reported that in the diagnosis of brain death, physicians used one or more investigations in addition to clinical examination and that in 100% of cases the investigation was an EEG, followed in 67% of cases by brain arteriography. Two EEG recordings seemed to be the most reliable method to validate brain death (as reported by 60% of physicians).
EEG sensitivity Very few recent data are available. The study by Paolin et al. in 1995 [18] showed a relatively low sensitivity of EEG in a population of 15 adults meeting the clinical criteria of brain death (absence of brainstem reflexes and absence of spontaneous respiration): EEG recording showed electrocerebral inactivity in only 8 patients and showed residual low-voltage activity in the other 7 patients (53% sensitivity). However, this study was performed in a small number of subjects using paper EEG devices; furthermore, the results seem discordant with other studies on this topic. In the study by Grigg [11] on 56 patients, meeting the clinical criteria of brain death, the sensitivity was better (80.6%). Three aspects were observed: low-voltage theta or beta activity in 9 patients (observed up to 72 hours after the clinical diagnosis), a sleep-coma appearance in two patients (up to 168 hours after the clinical diagnosis), and alpha coma in one patient (3 hours after having met the clinical criteria). None of these patients recovered. This study also involved only paper EEG recordings. Progression to digital EEG, sometimes coupled with video recording, has facilitated the identification of artifacts, and thus probably greatly improved the sensitivity of EEG. This was demonstrated in a recent German study [24], which compared somatosensory evoked potentials, EEG, transcranial Doppler, radionuclide cerebral perfusion study and cerebral angiography in 71 patients meeting the criteria of brain death. EEG was able to validate brain death (electrocerebral inactivity) in 67 cases out of 71 (94% of cases), similar to cerebral CT-angiography results and much better than the other techniques.
W. Szurhaj et al. Artifacts caused by resuscitation conditions (mains power, monitor screens, ballistocardiogram, etc.) can usually be easily eliminated. However, it is sometimes not possible to eliminate all artifacts, and the interpreting physician may therefore be unable to confirm the electrocerebral inactivity of the EEG recording. This explains in part the lack of sensitivity reported for EEG in certain studies. In some rare circumstances, such as open traumatic brain injury, EEG cannot be performed due to obvious technical difficulties.
EEG specificity The study conducted in the 1960s by the American EEG Society’s Ad Hoc Committee on EEG criteria for the determination of cerebral death revealed that, of 2650 cases of coma with presumably ‘‘isoelectric’’ EEGs, only three whose records satisfied the committee’s criteria showed any recovery of cerebral function. These three patients had received massive overdoses of nervous system depressants (barbiturates in 2 cases and meprobamate in one case). This study did not include children [1]. However, electrocerebral inactivity requires verification of the absence of certain conditions that could affect the degree of brain insult: • EEG is highly sensitive to drugs, especially barbiturates, which can lead to depression of electrogenesis or even a silent trace. This situation requires postponing the EEG until sedative drugs have been cleared from the patient’s body. The drugs concerned are barbiturates, benzodiazepines, anesthetics, especially propofol but also trichloroethylene, methoqualone, meprobamate and baclofen; the latter have a very long half-life and require a long period of time before being completely eliminated from the patient’s system [10,14,15,19,21]; • hypothermia is known to alter CNS function. It can slow down or depress electrogenesis but mainly in major hypothermia, below 28 ◦ C [7]. Coselli et al. [6] attempted to correlate the apparition of an ‘‘isoelectric’’ recording with peripheral body temperature, in 56 patients operated under hypothermia. They observed a wide temperature variability for the onset of ‘‘isoelectric’’ recording, with values ranging from 12.8 ◦ C to 28.6 ◦ C (rectal temperature). Furthermore, hypothermia can potentially alter the metabolism and clearance of certain administered medications. Unfortunately, to our knowledge, there is no study that has clarified the impact of hypothermia on electrogenesis in the specific context of brain death. Most experts agree that hypothermia > 30 ◦ C cannot be the cause of electrocerebral inactivity, yet in the absence of validated data, most guidelines require a body temperature above 35 ◦ C. Some metabolic disorders can have an impact on brain function: acute liver failure, severe hypoglycemia or hyponatremia. Since these conditions are reversible, it is important to correct them or to repeat the EEG before confirming electrocerebral inactivity.
EEG guidelines in the diagnosis of brain death Apart from these specific situations, EEG specificity is very good. Only a few cases of electrocerebral inactivity have been reported in patients who were not clinically dead, these having been observed before the widespread use of digital EEG.
Reproducibility of the EEG Buchner and Schuchardt [4] evaluated intra- and interexaminer reproducibility: they submitted 28 EEG recordings of patients with clinically validated brain death, to 8 neurologists, experienced in reading EEG; furthermore physicians had to interpret the same recording twice without being informed of this. Eighteen of the 28 recordings were interpreted in a concordant manner, reflecting electrocerebral inactivity, and 3 out of the 28 were interpreted as retaining some cortical electrical activity. Seven out of 28 recordings (25%) were the subject of discordant decisions. Furthermore, each physician interpreted in a different manner at least 1 recording between the 2 interpretations they carried out on the same EEG. This study was based on paper EEG recordings. To our knowledge there are no recent data on the reproducibility of digital EEG in the context of brain death. EEG is thus still a highly relevant investigation in the diagnosis of brain death. However, in France, because of the need to perform 2 tests respecting a 4-hour observation period, the influence of drugs on the recording and the fact that EEG is not available outside of routine working hours in most hospitals, this test has become less used in the diagnosis of brain death, cerebral CT-angiography being the examination of choice when available.
EEG recording conditions for the diagnosis of brain death In France, guidelines pertaining to EEG recording conditions in the confirmation of brain death were defined during the conference of the Société de Neurophysiologie Clinique in 1988, published in 1989 [5]. These recommendations were defined at a time when EEG recording was still acquired on paper-based devices. Since the 1990s, technological advances have allowed the emergence of digital EEG, which has progressively replaced, in routine practice, the older devices in most hospitals. Since then it has been necessary to redefine the criteria of brain death for digital EEG devices. A compared analysis of paper and digital EEG recordings was carried out simultaneously in 15 patients diagnosed with brain death [8]. This study highlighted increased utility for the digital EEG recording vs. paper EEG recording for one particular patient. The presence of fast pseudomicro-rhythms, with an amplitude around 2 V presented a challenge for interpretation, and in this case digital EEG seemed more sensitive than conventional paper-based EEG. This activity was extracerebral ‘‘noise’’ and was generated by the electrical components of digital devices, interference coming from the environment and monitoring equipment (e.g. electrodes and amplifier). Paper-based EEG devices did not have the capacity to transcribe these activities because
101 of the filter effect of the pen and galvanometer, which only detects a signal in the order of 1 V whereas digital EEG detects amplitudes of 0.15 V (i.e. 10 times more sensitive). This point was confirmed by a second study that consisted of generating a sinusoidal signal with modulating frequency and amplitude, highlighting that there was a major attenuation of the recorded signal for fast frequencies in conventional paper-based EEG, whereas no attenuation was observed for digital EEG, even for frequencies as high as 100 Hz. In the light of these results, the authors proposed technical guidelines, in addition to the criteria listed in French regulatory texts and those produced during the consensus conference for acquisition and reading of electrocerebral activity on digital EEG recordings. These guidelines were published by Sediri et al. in 2007 [20]. They complemented the 1989 guidelines from the SNCLF [5].
Required information before conducting the EEG Before proceeding with the EEG recording all relevant data must be collected: for example, patient’s first name, last name and date of birth, circumstances and origin of the coma, especially presumed time and date of coma onset and imaging results. The clinical examination report must detail the clinical brain death criteria (deep coma, absence of spontaneous respiration, absence of cranial nerve reflexes). Any clinical suspicion of pharmacological, biochemical or toxicological factors as well as metabolic factor or hypothermia should be mentioned. Data regarding the EEG recording must include: • date, time and location of the EEG recording and eventually status of the scalp; • drugs administered in the past 24 hours or systematically screened for in blood and urine samples; • body temperature and hemodynamic vital signs, especially mean arterial pressure, which should be maintained above 50 mmHg.
Technical requirements The recording must be conducted by a specialized technician or electrophysiology physician, these being the only persons qualified to identify and discard artifacts, implement appropriate means of recording, perform the necessary stimulation procedures and note all relevant data on the recording. The EEG recording must include at least 8 electrodes (standard electrodes or, ideally, needle electrodes): FP2, C4, O2, T4, FP1, C3, O1, T3, as well as a ground electrode; adding a median electrode is recommended. The resistance of each electrode must be between 100 and 10,000 [1]. Simultaneous ECG (in D1) and respiratory monitoring can help to identify some activity as artifacts. It is essential to have these simultaneous recordings during the entire EEG recording. Recording electrocerebral activity from one single channel, as is sometimes done in the ICU, is insufficient for the diagnosis of electrocerebral inactivity.
102 Recording should be conducted at a sampling frequency of at least 256 Hz, a resolution of at least 12 bits and with a high-pass filter set at 0.53 Hz. No digital filter below 70 Hz (aside from the 50 Hz filter) must be used since this could attenuate the fast cortical activity frequencies. In the case of persistent muscular artifacts, which could interfere with the interpretation of the EEG trace, it may be necessary to inject a neuromuscular blocking agent (curare) under the supervision of an anesthesiologist or physician familiar with the drug. In case of persistent artifacts, with potential doubt as to their cerebral origin, it might be useful to add an additional extracerebral channel, for example using 2 electrodes positioned on the patient’s hand. The EEG trace should include at least 30 minutes of good quality recording, in order to be interpreted without ambiguity. Visual, auditory, somatosensory (tactile and painful stimuli) stimulation procedures must be repeatedly performed and be clearly indicated on the recording (for somatosensory stimuli, indicating the point stimulated and discarding electrostatic shocks). The technician must note on the EEG tracing all stimulation procedures performed during the EEG recording. The system calibration is usually fully automated in digital EEG, but the integrity of the entire recording system must be tested by voluntarily creating artifacts (for example by touching each electrode). Artifacts encountered in the intensive care unit must be identified and if possible eliminated. The ballistocardiogram created by the ECG and diffusing to all EEG derivations, is often the most difficult to eliminate. It is possible to remove this artifact during recording if the patient’s head is kept turned to one side; if present, the interpreting physician will take this into account when reading the EEG, making sure that the artifact produced is perfectly synchronous to the QRS complex noted on the ECG channel. Other artifacts are caused by electrical parasites related to the 50 Hz power line noise and other critical care monitoring devices in the patient’s room. This type of artifact can be removed by using a reliable ground power outlet, unplugging airfluidized beds and choosing a different power outlet from the other monitoring devices used for patients’ critical care. The reverberation artifact can be eliminated by not placing the EEG device in front of other monitors present in the room.
Interpretation The EEG interpretation will be based on long distance bipolar montages with inter-electrode distances of 10 cm. We recommend a montage including frontal, central, temporal, occipital, right and left electrodes, for example: Fp2-C4, C4-O2, Fp1-C3, C3-O1, Fp2-T4, T4-O2, Fp1-T3, T3-O1. Reading settings should range between 3 and 5 v/mm (inclusive) with a speed of 20 s per display screen/page (i.e. 15 mm/s). A 30 mm/s speed (10 s per display screen) can be used to better appreciate the signal. High-frequency filters should not be set below 70 Hz, and low-frequency filters should not be set above 0.5 Hz. The notch filter set at 50 Hz can be used.
W. Szurhaj et al. The interpretation of the EEG will be easier with a good quality screen with a minimal resolution of 1280 × 1024. The ideal screen size for reading EEG recordings is 17 inches or more [20]. The vertical resolution will depend on the number of channels displayed (at least 10 including 8 for the EEG, 1 ECG and 1 respiratory). Flat screens have an advantage in terms of clarity. The printer must have a minimum resolution of 300 DPI. The interpretation can only be performed by a physician specialized in functional exploration of the central nervous system. The result must be given to those physicians authorized to deliver the diagnosis of brain death, and to them only. The validation of the irreversible nature of CNS alterations is based on the observation of persistent electrocerebral inactivity on the EEG recording. The EEG should yield 30 minutes of stable, clean and easily interpretable inactive recording. Electrocerebral inactivity is defined as the absence of EEG activity over 2 V, even during auditory and nociceptive stimulations procedures performed on both sides, without any possible objection. Specific conditions of EEG interpretation in the diagnosis of brain death are discussed below.
Hypothermia In France, the Société Franc ¸aise d’Anesthésie et de Réanimation, the Société de Réanimation de Langue Franc ¸aise, and Biomedicine Agency recommend a body temperature equal to or above 35 ◦ C before establishing the diagnosis of brain death. Some countries require significant absence of hypothermia, with a temperature above 32 ◦ C, but they do not use EEG. Moderate hypothermia with a body temperature above 30 ◦ C cannot yield an inactive EEG recording, but it could increase the abnormalities on the recording. We recommend a body temperature equal to or above 34 ◦ C in order to be able to confirm electrocerebral inactivity on the EEG. In the case of hypothermia below 34 ◦ C, the patient will have to be warmed up before performing the EEG recording. Further studies will be relevant to assess the impact of hypothermia between 30 and 34 ◦ C on brain electrogenesis in the diagnosis of brain death.
Observation period French laws do not mention a specific observation period after the initial event before validating the diagnosis of brain death, in contrast to other countries, mainly European ones [13]. However, the EEG can be misleading in showing falsepositive electrocerebral inactivity in the hours immediately following a cardiorespiratory arrest, before the reappearance of cerebral activity. For this reason, we recommend that EEG be performed respecting a 12-hour observation period after the cardiorespiratory arrest. In France, the law requires performing repeat EEG test with a 4-hour observation period between both tests, which is sometimes difficult in a patient presenting with hemodynamic instability. The 4-hour observation period between both EEG tests is indeed one of the main reasons why physicians nowadays tend to prefer cerebral CT-angiography in this context.
EEG guidelines in the diagnosis of brain death Very few data from the literature are available regarding changes observed between two consecutive EEG recordings in this context. All scientific societies, including the American Academy of Neurology (AAN), do not make it mandatory to perform two separate EEG tests. It seems quite unlikely that an EEG with electrocerebral inactivity, performed in the absence of sedation, hypothermia, or major metabolic disorders, would be significantly modified after a 4-hour observation period; however the test needs to be performed at a distance from the initial condition that led to the clinical diagnosis of brain death. The need to repeat the EEG test, when the latter has been performed at an appropriate distance from the initial event, could be challenged. We recommend that further studies be conducted to evaluate the changes in EEG recording between two repeat tests. The goal would be to avoid the 4-hour inter-examination observation period, which can sometimes limit the use of EEG in certain situations, and can delay organ harvesting. While further studies are awaited to clarify these issues, we recommend repeating the EEG test while respecting an inter-examination observation period of at least 4 hours between both tests (measured from the beginning time of each EEG).
Medication The question of drug plasma levels for sedative drugs administered to the patient is an important and difficult issue, and is not mentioned in the French regulatory text of 1996. Some drugs, such as barbiturates, can have a long clearance level according to the drug’s half-life, and as such it is not always possible to wait for drug plasma levels to return to zero. The American Academy of Neurology (2005) stipulates: ‘‘If intoxicants such as barbiturates, benzodiazepines, or opioids are present, levels need not be zero, but should be in a range that would not normally be expected to interfere significantly with consciousness’’. Other scientific societies, and especially the Biomedicine Agency in its latest report on removing donated organs recommends simply that drug plasma levels be below therapeutic range. Techniques based on cerebral blood flow, not being influenced by sedative drugs, are recommended rather than EEG in this context. Furthermore, the study of evoked potentials (auditory and somatosensory) is an electrophysiological technique less sensitive to sedative drugs and hypothermia and could help determine the absence of cortical and sub-cortical activity, even though it has no medical-legal value in France today [12]. When it is impossible to use these alternative ancillary exams, it is preferable to wait for drug plasma levels results to come back before interpreting the EEG and wait for these levels to be validated as not interfering in a significant manner in cerebral electrogenesis.
Specificities for the diagnosis of brain death in children In France, there is no specific regulatory text for the diagnosis of brain death in children. However experts agree that adult criteria cannot be applied to young children [22].
103 The American Academy of Pediatrics (AAP) recently (2011) published its guidelines [17]. In the United States, the diagnosis of brain death is made solely on clinical criteria and the apnea test. ‘‘Ancillary studies (electroencephalogram and radionuclide cerebral blood flow) are not required to establish brain death and are not a substitute for the neurologic examination. However ancillary studies may be used to assist the clinician in making the diagnosis of brain death (i) when components of the examination or apnea testing cannot be completed safely due to the underlying medical condition of the patient; (ii) if there is uncertainty about the results of the neurologic examination; (iii) if a medication effect may be present; or (iv) to reduce the interexamination observation period’’. Experts all agree that the younger the child the longer the inter-examination observation period should be between the clinical examinations leading to the diagnosis of brain death: AAP recommends an observation period of 24 hours for term newborns (37 weeks gestational age) to 30 days of age, and 12 hours for infants and children (> 30 days to 18 years). Performing an ancillary exam (for example EEG) can reduce this observation period. Thus, the Société Franc ¸aise d’Anesthésie Réanimation published its guidelines in 2005 [3]: • ‘‘in children, the diagnosis of brain death is based on different criteria than in adults, after having excluded, just like in adults, confounding factors [3]; • in preterm newborns and term newborns under 7 days of life, because of cerebral immaturity, EEG is not a reliable indicator of brain death, and physicians should usually rely on cerebral angiography; • between the age of 7 days and 2 months, it is recommended to perform two clinical examinations and 2 EEGs with an inter-examination observation period of 48 hours, except in cases of anoxic brain injury; • between the age of 2 months and 1 year, it is recommended to perform two clinical examinations and 2 EEGs with an inter-examination observation period of 24 hours, except in cases of anoxic brain injury; • beyond the age of 1 year, criteria are similar to those applied to adults.’’ Some studies [2] suggest that there is no evidence to justify using different observation periods in adults and children above the age of 1 month. As a matter of fact, there are no reported cases of children who recovered neurological functions after having met all the criteria of brain death applied to adults [17]. A review of the literature based on 12 studies (published in the guidelines of the American Academy of Pediatrics in 2011) [17], on a cohort of 485 children suspected of brain death, is reported in these guidelines. It evaluated the sensitivity of EEG at 76% in children; this sensitivity increased to 89% with a repeat EEG test. Two false-positive tests were reported each time children were being given barbiturates. The sensitivity of EEG was as good as cerebral CT-angiography in children over the age of 1 month, but it was lower in the group of children under the age of 1 month (40% vs. 63%). Based on these data, we have established the following guidelines:
104 • the clinical examination and specific brain death criteria must be noted on the EEG request and must be repeated; • in preterm newborns and term newborns < 7 days of life, because of cerebral immaturity, EEG is not a reliable indicator of brain death, and it is recommended to use cerebral CT-angiography; • between the age of 7 days and 1 month, it is recommended to perform two EEG tests, respecting a 48-hour interexamination observation period; • between 1 month and 1 year: the recommended interexamination observation period is 24 hours; • above the age of 1 year: the recommended interexamination observation period is identical to that of adults. However these recommendations on age and observation periods are based on empirical knowledge, and we recommend conducting further studies to provide evidence-based data, in order to better refine ages and observation periods. In the specific context of infants, the interpreting physician must be experienced in neonatal EEG.
Conclusion EEG is a test used to validate brain death as listed in regulatory texts, adding evidence to the clinical criteria of brain death, but in no circumstance can it be a substitute to these clinical criteria. Two EEG recordings, respecting a 4-hour inter-examination observation period, are necessary. In this situation, electrocerebral inactivity is considered when EEG during a 30-minute, good quality recording evidences electrical inactivity defined as the absence of cerebral activity above 2 V, excluding the possible influence of sedation, metabolic disorders or hypothermia. In case of impregnation by sedative drugs, cerebral CTangiography will be the examination of choice. Criteria for the diagnosis of brain death in newborns and infants still need to be better clarified.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] American Clinical Neurophysiology Society. Guideline 3: minimum technical standards for EEG recording in suspected cerebral death. Am J Electroneurodiagnostic Technol 2006; 46:211—9. [2] Ashwal S. Brain death in the newborn. Current perspectives. Clin Perinatol 1997;24:859—82. [3] Boulard G, Guiot P, Pottecher T, Tenaillon A. Prise en charge des sujets en état de mort encéphalique dans l’optique d’un prélèvement d’organes. Ann Fr Anesth Reanim 2005;24: 836—43. [4] Buchner H, Schuchardt V. Reliability of electroencephalogram in the diagnosis of brain death. Eur Neurol 1990;30:138—41. [5] Clinique Bdlsdn. Recommandations quant aux conditions de réalisation d’un enregistrement EEG exigible pour le constat d’une mort cérébrale. Neurophysiol Clin 1989;19:339—41.
W. Szurhaj et al. [6] Coselli JS, Crawford ES, Beall Jr AC, Mizrahi EM, Hess KR, Patel VM. Determination of brain temperatures for safe circulatory arrest during cardiovascular operation. Ann Thorac Surg 1988;45:638—42. [7] Danzl DF, Pozos RS. Accidental hypothermia. N Engl J Med 1994;331:1756—60. [8] Derambure P, Caillez S, Bourriez JL, JDG. Utilisation de l’EEG numérisé dans le diagnostic de la mort encéphalique. L’évaluation neurophysiologique des comas, de la mort encéphalique et des états végétatifs. Solal E, editor: Guérit JM; 2001. p. 271—87. [9] Fischer C. [The use of EEG in the diagnosis of brain death in France]. Neurophysiol Clin 1997;27:373—82. [10] Garcia-Larrea L, Fischer C, Artru F. [Effect of anesthetics on sensory evoked potentials]. Neurophysiol Clin 1993;23:141—62 [Effet des anesthésiques sur les potentiels évoqués sensoriels]. [11] Grigg MM, Kelly MA, Celesia GG, Ghobrial MW, Ross ER. Electroencephalographic activity after brain death. Arch Neurol 1987;44:948—54. [12] Guérit JM. Apport pronostique des potentiels évoqués en unité de soins intensifs. Ann Fr Anesth Reanim 2004;23:99—101. [13] Haupt WF, Rudolf J. European brain death codes: a comparison of national guidelines. J Neurol 1999;246:432—7. [14] Meinitzer A, Kalcher K, Gartner G, Halwachs-Baumann G, Marz W, Stettin M. Drugs and brain death diagnostics: determination of drugs capable of inducing EEG zero line. Clin Chem Lab Med 2008;46:1732—8. [15] Mellerio F. EEG changes during acute intoxication with trichlorethylene. Electroencephalogr Clin Neurophysiol 1970; 29:101. [16] Morenski JD, Oro JJ, Tobias JD, Singh A. Determination of death by neurological criteria. J Intensive Care Med 2003;18: 211—21. [17] Nakagawa TA, Ashwal S, Mathur M, Mysore M, Society of Critical Care Medicine SoCC, Section on Neurology of American Academy of P, et al. Clinical report-Guidelines for the determination of brain death in infants and children: an update of the 1987 task force recommendations. Pediatrics 2011;128: e720—40. [18] Paolin A, Manuali A, Di Paola F, Boccaletto F, Caputo P, Zanata R, et al. Reliability in diagnosis of brain death. Intensive Care Med 1995;21:657—62. [19] Powner DJ. Drug-associated isoelectric EEGs. A hazard in braindeath certification. JAMA 1976;236:1123. [20] Sediri H, Bourriez JL, Derambure P. Place de l’EG dans le diagnostic de mort cérébrale. Rev Neurol (Paris) 2007;163: 248—53. [21] Sullivan R, Hodgman MJ, Kao L, Tormoehlen LM. Baclofen overdose mimicking brain death. Clin Toxicol 2012;50:141—4. [22] Vecchierini-Blineau MF, Moussalli-Salefranque F. [Diagnosis of brain death in the newborn and the child]. Neurophysiol Clin 1992;22:179—90 [Diagnostic de la mort cérébrale chez le nouveau-né et l’enfant]. [23] Vivien B, Haralambo MS, Riou B. Barotraumatisme lors du test d’apnée chez des patients en état de mort encéphalique. Ann Fr Anesth Reanim 2001;20:370—3. [24] Welschehold S, Boor S, Reuland K, Thomke F, Kerz T, Reuland A, et al. Technical aids in the diagnosis of brain death: a comparison of SEP, AEP, EEG, TCD and CT angiography. Deutsch Arztebl Int 2012;109:624—30. [25] Wijdicks EF. Determining brain death in adults. Neurology 1995;45:1003—11. [26] Wijdicks EF. Practice parameters for determining brain death in adults (summary statement). The Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1995;45:1012—4. [27] Wijdicks EF. Brain death worldwide: accepted fact but no global consensus in diagnostic criteria. Neurology 2002;58:20—5.
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REVIEW/MISE AU POINT
EEG guidelines in the diagnosis of brain death L’EEG dans le diagnostic de mort cérébrale W. Szurhaj a,b,∗, M.-D. Lamblin a, A. Kaminska c, H. Sediri a a
Service de neurophysiologie clinique, CHRU, 59037 Lille cedex, France Faculté de médecine, Université Lille 2, Lille, France c Laboratoire de neurophysiologie clinique, Hôpital Necker—Enfants Malades, AP—HP, Paris, France b
Received 5 November 2014; accepted 9 November 2014 Available online 14 January 2015
KEYWORDS Electroencephalography; EEG; Brain death; Recommendations; Technical aspects
MOTS CLÉS Électroencéphalogramme ; EEG ;
∗
Summary In France, for the determination and diagnostic validation of brain death the law requires either two EEG recordings separated by a 4-hour observation period, both showing electrocerebral inactivity; or cerebral angiography examination. Since EEG is available in most hospitals and clinics, it is often used in this indication, at the patient’s bedside, especially in the context of organ donation. However, very precise methodology must be followed. The last French guidelines date back to 1989, before the development of digital EEG recording. We present the new guidelines from the Société de Neurophysiologie Clinique de Langue Franc ¸aise. Electrocerebral inactivity may be confirmed when a 30-minute good quality EEG recording shows complete electrocerebral silence, defined as no cerebral activity greater than 2 uV, having first ruled out the possible influence of sedative drugs, metabolic disorders or hypothermia. In the presence of sedative drugs, CT brain angiography will be the gold standard test for this diagnosis. In the newborn, the utmost caution is indicated since electrocerebral inactivity can be observed in the absence of cerebral death. In the infant, the criterion for the observation period to be respected between both EEG recordings needs to be more clearly refined. © 2015 Elsevier Masson SAS. All rights reserved.
Résumé En France, la loi exige que le diagnostic clinique de mort cérébrale soit confirmé par deux EEG inactifs réalisés à 4 heures d’intervalle ou une angiographie cérébrale. La disponibilité de l’EEG dans la plupart des centres hospitaliers et sa facilité de réalisation au lit du patient en font toujours un examen très utilisé dans cette indication, notamment dans le cadre des prélèvements d’organes. Sa réalisation exige toutefois une méthodologie
Corresponding author. Service de neurophysiologie clinique, CHRU, 59037 Lille cedex, France. Tel.: +33 06 76 76 32 07. E-mail address: [email protected] (W. Szurhaj).
http://dx.doi.org/10.1016/j.neucli.2014.11.005 0987-7053/© 2015 Elsevier Masson SAS. All rights reserved.
98
W. Szurhaj et al.
Mort cérébrale ; Recommandations ; Aspects techniques
précise. Les dernières recommandations franc ¸aises dataient de 1989, avant l’avènement de l’EEG numérisé. Nous présentons ici les nouvelles recommandations de la Société de neurophysiologie clinique de langue franc ¸aise. L’EEG sera considéré « inactif » lorsqu’un tracé de 30 minutes, de bonne qualité, montre un silence électrique, défini comme l’absence d’activité cérébrale d’une amplitude supérieure à 2 V, à la condition d’exclure l’influence possible de la sédation, de troubles métaboliques et d’une hypothermie. En cas d’imprégnation par des substances sédatives, l’angioscanner sera préféré. En contexte néo-natal, une grande prudence est nécessaire, un tracé inactif pouvant être observé en l’absence de mort encéphalique. Chez le nourrisson, les critères d’intervalle entre les deux EEG devront encore être mieux définis. © 2015 Elsevier Masson SAS. Tous droits réservés.
Abbreviations
CT ECG EEG
computed tomography electrocardiogram electroencephalogram
Summary of guidelines It is mandatory for the physician interpreting EEG in the context of brain death to obtain the maximum amount of data: • before performing an EEG, essential clinical data must be collected: patient’s last name, first name and date of birth, circumstances and origin of the coma, especially date and time of the presumed onset of the coma, and imaging results; • the clinical examination (neurologic assessment) must specify brain death criteria (deep coma; absence of spontaneous respiration; absence of brainstem reflexes); • any clinical suspicion of pharmacological, biochemical or toxic factors, as well as metabolic disturbance or hypothermia should be mentioned in the evaluation report; • data regarding the EEG recording should include: date, time and location of the EEG recording and possibly scalp condition. Drugs administered in the preceding 24 hours or drugs screened for in blood and urine should be indicated, as well as body temperature and hemodynamic parameters, especially mean arterial pressure, which should be maintained above 50 mmHg. The execution parameters must be rigorously observed: • the recording should be performed by a specialized technician, or physician who is board-certified in electroencephalography, these being the only persons qualified to identify and reject artifacts, implement the required polygraphy set-up, perform necessary activation procedures and document all relevant data on the recording;
• EEG recording should include a minimum of eight scalp electrodes (standard ones or ideally needle electrodes): FP2, C4, O2, T4, FP1, C3, O1, T3. Cz is recommended; • simultaneous ECG (in D1) and respiratory movement recording can help identify certain activities as artifacts. It seems essential to be able to have these two recordings during the entire EEG duration; • impedances for each electrode must be between 100 and 10,000 . The recording will be performed at a sampling rate of at least 256 Hz, and the high-pass filter should be set at 0.53 Hz. Digital filters below 70 Hz should not be used (apart from the notch filter at 50 Hz), as this could attenuate high-frequency brain waves; • the EEG tracing should include at least 30 minutes of good quality recording in order to be properly interpreted; • auditory and bilateral somatosensory stimuli (touch and pain) should be repeatedly performed, and be clearly indicated on the recording (for somatosensory stimuli, indication of the stimulated point and excluding electrostatic shocks); • the technician must note on the recording all events that occur during the examination; • system calibration is usually automated in digital EEG; however the integrity of the entire recording system should be tested by voluntarily creating artifacts (shaking the connecting leads of the electrodes for example); • in order to validate the lack of electrical activity on the EEG, we recommend maintaining the patient’s body temperature above 34 ◦ C (minimum recommended). In the case of hypothermia, with a temperature below 34 ◦ C, the patient’s body will need to be warmed up before proceeding with the EEG; • we recommend that the EEG be performed at least 12 hours after cardiorespiratory arrest; • it is necessary to repeat the EEG with a minimum of 4 hours between the two examinations (minimum of 4 hours calculated from the beginning of each recording); • since techniques based on the study of intracerebral blood flow (cerebral angiography) are not influenced by sedative medications, we recommend using these techniques rather than EEG in this situation; • if it is impossible to use these alternative techniques, the EEG interpretation must take into account the sedative drugs previously administered, and eventually residual drug levels in the blood sample.
EEG guidelines in the diagnosis of brain death The interpretation conditions should allow for the best interpretation possible, without any possible objections: • electrocerebral inactivity (term of reference rather than using ‘‘flat-lined’’, ‘‘null’’, ‘‘isoelectric’’) is defined by the absence of cerebral activity above 2 V amplitude, even when auditory and nociceptive stimuli are performed in a bilateral manner; • the interpretation of the EEG will be easier on a good quality display screen with a minimum resolution of 1280 × 1024. The optimal screen size for proper reading is 17 inches or more; • for an optimal interpretation of the recording, the reading settings should range between 3 and 5 v/mm (inclusive) with a speed of 20 s per display screen/page (i.e. 15 mm/s). A 30 mm/s speed (10 s per display screen) can be used to better appreciate the signal; • for paper traces, the printer should have a minimum resolution of 300 DPI; • the interpretation should be carried out using long distance montages, without filters; • the interpretation report can only be written by a physician specialized in functional exploration of the central nervous system. EEG results should only be communicated to physicians qualified to confirm a diagnosis of brain death, and no one else. In children, due to brain immaturity, specific recommendations should be taken into account: • the clinical examination and precise brain death criteria should be detailed on the EEG request and be repeated; • in premature babies and newborns under 7 days of life, because of brain immaturity, EEG is not a reliable indicator of brain death and cerebral angiography should be used; • between the age of 7 days and 1 month, it is recommended to perform two EEGs separated by a 48-hour interval and above all to take into account clinical criteria; • beyond the age of 1 month and up to 1 year, the recommended interval between the two EEGs is 24 hours; • beyond the age of 1 year, the recommended delay between two examinations is similar to that applied to adults (i.e. 4 hours); • under the age of 2 months, the interpreting physician must be experienced in performing EEG in newborns and infants.
99 both cerebral perfusion scintigraphy confirming irreversible cerebral insult and EEG showing electrocerebral inactivity are mandatory for the diagnosis of brain death. In Australia and in some Asian countries, clinical criteria based on the absence of brainstem reflexes are applied. In summary, the major differences between criteria listed in the different guidelines [27] are: the number of examining physicians required to confirm brain death, their seniority and level of experience; additional examinations are sometimes mandatory and sometimes only recommended; the duration of the observation period after declaration of brain death varies, the most usual being around 24 hours; the apnea test is the object of controversy because of potentially noxious consequences on internal organs [23]. Some countries, in which organ transplantation is not performed (some African countries for example), do not have brain death criteria.
French laws In France, the last regulatory text still in application today was published in 1996. It governs the procedures and necessary conditions for the diagnosis of brain death and also organ donation. Decree no 96-1041 of December 2, 1996 relative to the diagnosis of death, prior to removing organs, tissues or cells for therapeutic or scientific purposes and modifying the Public Health Code. Section 3. —– Removing organs from a deceased patient. Sub-section 1. —– Validation of brain death before removing organs for therapeutic or scientific purposes. Art. R. 671-7-1. —– If the person is in cardiac and respiratory arrest, brain death can only be validated if the three following clinical criteria are simultaneously observed: • lack of any evidence of consciousness and of spontaneous motor activity; • absence of all brainstem reflexes; • total absence of spontaneous respiration. Art. R. 671-7-2. —– If the person, whose death was clinically validated, is assisted via mechanical ventilation and conserves hemodynamic functions, the absence of spontaneous breathing is verified using the hypercapnia test. Furthermore, in addition to the three clinical criteria mentioned in the article R. 671-7-1, the following tests are mandatory to validate the irreversible nature of the brain insult:
Full-length guidelines The utility of EEG in the diagnosis of brain death is regarded differently in different countries. In the United States, EEG is recommended but is not mandatory [16,25,26]. In Canada, EEG is no longer recommended for this indication. In Europe, an EEG laboratory test to validate the diagnosis of brain death is not recommended in all countries. In several countries, the apnea test is performed, to look for hypercapnia based on an increase of PCO2 > 20 mmHg compared to normal. The duration of the observation period between the initial event and the EEG varies from 0 to 48 hours, especially when anoxia is the cause of brain death. In Japan,
• either two electroencephalogram recordings showing electrocerebral inactivity, respecting a 4-hour observation period between both tests, conducted with maximal amplification on a 30-minute recording; the result must be immediately recorded by the physician who interpreted the recording; • or cerebral arteriography showing lack of blood flow to the brain; the radiologist who interpreted the imaging exam must immediately record the result. Art. R. 671-7-3.-III. —– When brain death has been validated for a person undergoing mechanical ventilation
100 retaining hemodynamic functions, the brain death report indicates the results of the concordant clinical observations of two physicians adhering to the conditions mentioned in article L. 671-10. Furthermore, it mentions the result of examinations as defined in the 1st or 2nd addendum of article R. 671-7-2, as well as the date and time of the report. The report is signed by the two physicians mentioned above. The EEG in this last text appears as one of the mandatory examinations, along with cerebral arteriography (or more recently cerebral CT-angiography), necessary to confirm the irreversible and definite nature of the brain destruction. Specific conditions of duration, amplification and observation period between the examinations are clearly defined, but refer to traditional EEG paper recordings.
Advantages and limits of EEG in the early diagnosis of brain death The main advantage of EEG is its non-invasive, reproducible nature, and it is easily available in most hospitals. In a study conducted in France in 1997, C. Fischer [9] reported that in the diagnosis of brain death, physicians used one or more investigations in addition to clinical examination and that in 100% of cases the investigation was an EEG, followed in 67% of cases by brain arteriography. Two EEG recordings seemed to be the most reliable method to validate brain death (as reported by 60% of physicians).
EEG sensitivity Very few recent data are available. The study by Paolin et al. in 1995 [18] showed a relatively low sensitivity of EEG in a population of 15 adults meeting the clinical criteria of brain death (absence of brainstem reflexes and absence of spontaneous respiration): EEG recording showed electrocerebral inactivity in only 8 patients and showed residual low-voltage activity in the other 7 patients (53% sensitivity). However, this study was performed in a small number of subjects using paper EEG devices; furthermore, the results seem discordant with other studies on this topic. In the study by Grigg [11] on 56 patients, meeting the clinical criteria of brain death, the sensitivity was better (80.6%). Three aspects were observed: low-voltage theta or beta activity in 9 patients (observed up to 72 hours after the clinical diagnosis), a sleep-coma appearance in two patients (up to 168 hours after the clinical diagnosis), and alpha coma in one patient (3 hours after having met the clinical criteria). None of these patients recovered. This study also involved only paper EEG recordings. Progression to digital EEG, sometimes coupled with video recording, has facilitated the identification of artifacts, and thus probably greatly improved the sensitivity of EEG. This was demonstrated in a recent German study [24], which compared somatosensory evoked potentials, EEG, transcranial Doppler, radionuclide cerebral perfusion study and cerebral angiography in 71 patients meeting the criteria of brain death. EEG was able to validate brain death (electrocerebral inactivity) in 67 cases out of 71 (94% of cases), similar to cerebral CT-angiography results and much better than the other techniques.
W. Szurhaj et al. Artifacts caused by resuscitation conditions (mains power, monitor screens, ballistocardiogram, etc.) can usually be easily eliminated. However, it is sometimes not possible to eliminate all artifacts, and the interpreting physician may therefore be unable to confirm the electrocerebral inactivity of the EEG recording. This explains in part the lack of sensitivity reported for EEG in certain studies. In some rare circumstances, such as open traumatic brain injury, EEG cannot be performed due to obvious technical difficulties.
EEG specificity The study conducted in the 1960s by the American EEG Society’s Ad Hoc Committee on EEG criteria for the determination of cerebral death revealed that, of 2650 cases of coma with presumably ‘‘isoelectric’’ EEGs, only three whose records satisfied the committee’s criteria showed any recovery of cerebral function. These three patients had received massive overdoses of nervous system depressants (barbiturates in 2 cases and meprobamate in one case). This study did not include children [1]. However, electrocerebral inactivity requires verification of the absence of certain conditions that could affect the degree of brain insult: • EEG is highly sensitive to drugs, especially barbiturates, which can lead to depression of electrogenesis or even a silent trace. This situation requires postponing the EEG until sedative drugs have been cleared from the patient’s body. The drugs concerned are barbiturates, benzodiazepines, anesthetics, especially propofol but also trichloroethylene, methoqualone, meprobamate and baclofen; the latter have a very long half-life and require a long period of time before being completely eliminated from the patient’s system [10,14,15,19,21]; • hypothermia is known to alter CNS function. It can slow down or depress electrogenesis but mainly in major hypothermia, below 28 ◦ C [7]. Coselli et al. [6] attempted to correlate the apparition of an ‘‘isoelectric’’ recording with peripheral body temperature, in 56 patients operated under hypothermia. They observed a wide temperature variability for the onset of ‘‘isoelectric’’ recording, with values ranging from 12.8 ◦ C to 28.6 ◦ C (rectal temperature). Furthermore, hypothermia can potentially alter the metabolism and clearance of certain administered medications. Unfortunately, to our knowledge, there is no study that has clarified the impact of hypothermia on electrogenesis in the specific context of brain death. Most experts agree that hypothermia > 30 ◦ C cannot be the cause of electrocerebral inactivity, yet in the absence of validated data, most guidelines require a body temperature above 35 ◦ C. Some metabolic disorders can have an impact on brain function: acute liver failure, severe hypoglycemia or hyponatremia. Since these conditions are reversible, it is important to correct them or to repeat the EEG before confirming electrocerebral inactivity.
EEG guidelines in the diagnosis of brain death Apart from these specific situations, EEG specificity is very good. Only a few cases of electrocerebral inactivity have been reported in patients who were not clinically dead, these having been observed before the widespread use of digital EEG.
Reproducibility of the EEG Buchner and Schuchardt [4] evaluated intra- and interexaminer reproducibility: they submitted 28 EEG recordings of patients with clinically validated brain death, to 8 neurologists, experienced in reading EEG; furthermore physicians had to interpret the same recording twice without being informed of this. Eighteen of the 28 recordings were interpreted in a concordant manner, reflecting electrocerebral inactivity, and 3 out of the 28 were interpreted as retaining some cortical electrical activity. Seven out of 28 recordings (25%) were the subject of discordant decisions. Furthermore, each physician interpreted in a different manner at least 1 recording between the 2 interpretations they carried out on the same EEG. This study was based on paper EEG recordings. To our knowledge there are no recent data on the reproducibility of digital EEG in the context of brain death. EEG is thus still a highly relevant investigation in the diagnosis of brain death. However, in France, because of the need to perform 2 tests respecting a 4-hour observation period, the influence of drugs on the recording and the fact that EEG is not available outside of routine working hours in most hospitals, this test has become less used in the diagnosis of brain death, cerebral CT-angiography being the examination of choice when available.
EEG recording conditions for the diagnosis of brain death In France, guidelines pertaining to EEG recording conditions in the confirmation of brain death were defined during the conference of the Société de Neurophysiologie Clinique in 1988, published in 1989 [5]. These recommendations were defined at a time when EEG recording was still acquired on paper-based devices. Since the 1990s, technological advances have allowed the emergence of digital EEG, which has progressively replaced, in routine practice, the older devices in most hospitals. Since then it has been necessary to redefine the criteria of brain death for digital EEG devices. A compared analysis of paper and digital EEG recordings was carried out simultaneously in 15 patients diagnosed with brain death [8]. This study highlighted increased utility for the digital EEG recording vs. paper EEG recording for one particular patient. The presence of fast pseudomicro-rhythms, with an amplitude around 2 V presented a challenge for interpretation, and in this case digital EEG seemed more sensitive than conventional paper-based EEG. This activity was extracerebral ‘‘noise’’ and was generated by the electrical components of digital devices, interference coming from the environment and monitoring equipment (e.g. electrodes and amplifier). Paper-based EEG devices did not have the capacity to transcribe these activities because
101 of the filter effect of the pen and galvanometer, which only detects a signal in the order of 1 V whereas digital EEG detects amplitudes of 0.15 V (i.e. 10 times more sensitive). This point was confirmed by a second study that consisted of generating a sinusoidal signal with modulating frequency and amplitude, highlighting that there was a major attenuation of the recorded signal for fast frequencies in conventional paper-based EEG, whereas no attenuation was observed for digital EEG, even for frequencies as high as 100 Hz. In the light of these results, the authors proposed technical guidelines, in addition to the criteria listed in French regulatory texts and those produced during the consensus conference for acquisition and reading of electrocerebral activity on digital EEG recordings. These guidelines were published by Sediri et al. in 2007 [20]. They complemented the 1989 guidelines from the SNCLF [5].
Required information before conducting the EEG Before proceeding with the EEG recording all relevant data must be collected: for example, patient’s first name, last name and date of birth, circumstances and origin of the coma, especially presumed time and date of coma onset and imaging results. The clinical examination report must detail the clinical brain death criteria (deep coma, absence of spontaneous respiration, absence of cranial nerve reflexes). Any clinical suspicion of pharmacological, biochemical or toxicological factors as well as metabolic factor or hypothermia should be mentioned. Data regarding the EEG recording must include: • date, time and location of the EEG recording and eventually status of the scalp; • drugs administered in the past 24 hours or systematically screened for in blood and urine samples; • body temperature and hemodynamic vital signs, especially mean arterial pressure, which should be maintained above 50 mmHg.
Technical requirements The recording must be conducted by a specialized technician or electrophysiology physician, these being the only persons qualified to identify and discard artifacts, implement appropriate means of recording, perform the necessary stimulation procedures and note all relevant data on the recording. The EEG recording must include at least 8 electrodes (standard electrodes or, ideally, needle electrodes): FP2, C4, O2, T4, FP1, C3, O1, T3, as well as a ground electrode; adding a median electrode is recommended. The resistance of each electrode must be between 100 and 10,000 [1]. Simultaneous ECG (in D1) and respiratory monitoring can help to identify some activity as artifacts. It is essential to have these simultaneous recordings during the entire EEG recording. Recording electrocerebral activity from one single channel, as is sometimes done in the ICU, is insufficient for the diagnosis of electrocerebral inactivity.
102 Recording should be conducted at a sampling frequency of at least 256 Hz, a resolution of at least 12 bits and with a high-pass filter set at 0.53 Hz. No digital filter below 70 Hz (aside from the 50 Hz filter) must be used since this could attenuate the fast cortical activity frequencies. In the case of persistent muscular artifacts, which could interfere with the interpretation of the EEG trace, it may be necessary to inject a neuromuscular blocking agent (curare) under the supervision of an anesthesiologist or physician familiar with the drug. In case of persistent artifacts, with potential doubt as to their cerebral origin, it might be useful to add an additional extracerebral channel, for example using 2 electrodes positioned on the patient’s hand. The EEG trace should include at least 30 minutes of good quality recording, in order to be interpreted without ambiguity. Visual, auditory, somatosensory (tactile and painful stimuli) stimulation procedures must be repeatedly performed and be clearly indicated on the recording (for somatosensory stimuli, indicating the point stimulated and discarding electrostatic shocks). The technician must note on the EEG tracing all stimulation procedures performed during the EEG recording. The system calibration is usually fully automated in digital EEG, but the integrity of the entire recording system must be tested by voluntarily creating artifacts (for example by touching each electrode). Artifacts encountered in the intensive care unit must be identified and if possible eliminated. The ballistocardiogram created by the ECG and diffusing to all EEG derivations, is often the most difficult to eliminate. It is possible to remove this artifact during recording if the patient’s head is kept turned to one side; if present, the interpreting physician will take this into account when reading the EEG, making sure that the artifact produced is perfectly synchronous to the QRS complex noted on the ECG channel. Other artifacts are caused by electrical parasites related to the 50 Hz power line noise and other critical care monitoring devices in the patient’s room. This type of artifact can be removed by using a reliable ground power outlet, unplugging airfluidized beds and choosing a different power outlet from the other monitoring devices used for patients’ critical care. The reverberation artifact can be eliminated by not placing the EEG device in front of other monitors present in the room.
Interpretation The EEG interpretation will be based on long distance bipolar montages with inter-electrode distances of 10 cm. We recommend a montage including frontal, central, temporal, occipital, right and left electrodes, for example: Fp2-C4, C4-O2, Fp1-C3, C3-O1, Fp2-T4, T4-O2, Fp1-T3, T3-O1. Reading settings should range between 3 and 5 v/mm (inclusive) with a speed of 20 s per display screen/page (i.e. 15 mm/s). A 30 mm/s speed (10 s per display screen) can be used to better appreciate the signal. High-frequency filters should not be set below 70 Hz, and low-frequency filters should not be set above 0.5 Hz. The notch filter set at 50 Hz can be used.
W. Szurhaj et al. The interpretation of the EEG will be easier with a good quality screen with a minimal resolution of 1280 × 1024. The ideal screen size for reading EEG recordings is 17 inches or more [20]. The vertical resolution will depend on the number of channels displayed (at least 10 including 8 for the EEG, 1 ECG and 1 respiratory). Flat screens have an advantage in terms of clarity. The printer must have a minimum resolution of 300 DPI. The interpretation can only be performed by a physician specialized in functional exploration of the central nervous system. The result must be given to those physicians authorized to deliver the diagnosis of brain death, and to them only. The validation of the irreversible nature of CNS alterations is based on the observation of persistent electrocerebral inactivity on the EEG recording. The EEG should yield 30 minutes of stable, clean and easily interpretable inactive recording. Electrocerebral inactivity is defined as the absence of EEG activity over 2 V, even during auditory and nociceptive stimulations procedures performed on both sides, without any possible objection. Specific conditions of EEG interpretation in the diagnosis of brain death are discussed below.
Hypothermia In France, the Société Franc ¸aise d’Anesthésie et de Réanimation, the Société de Réanimation de Langue Franc ¸aise, and Biomedicine Agency recommend a body temperature equal to or above 35 ◦ C before establishing the diagnosis of brain death. Some countries require significant absence of hypothermia, with a temperature above 32 ◦ C, but they do not use EEG. Moderate hypothermia with a body temperature above 30 ◦ C cannot yield an inactive EEG recording, but it could increase the abnormalities on the recording. We recommend a body temperature equal to or above 34 ◦ C in order to be able to confirm electrocerebral inactivity on the EEG. In the case of hypothermia below 34 ◦ C, the patient will have to be warmed up before performing the EEG recording. Further studies will be relevant to assess the impact of hypothermia between 30 and 34 ◦ C on brain electrogenesis in the diagnosis of brain death.
Observation period French laws do not mention a specific observation period after the initial event before validating the diagnosis of brain death, in contrast to other countries, mainly European ones [13]. However, the EEG can be misleading in showing falsepositive electrocerebral inactivity in the hours immediately following a cardiorespiratory arrest, before the reappearance of cerebral activity. For this reason, we recommend that EEG be performed respecting a 12-hour observation period after the cardiorespiratory arrest. In France, the law requires performing repeat EEG test with a 4-hour observation period between both tests, which is sometimes difficult in a patient presenting with hemodynamic instability. The 4-hour observation period between both EEG tests is indeed one of the main reasons why physicians nowadays tend to prefer cerebral CT-angiography in this context.
EEG guidelines in the diagnosis of brain death Very few data from the literature are available regarding changes observed between two consecutive EEG recordings in this context. All scientific societies, including the American Academy of Neurology (AAN), do not make it mandatory to perform two separate EEG tests. It seems quite unlikely that an EEG with electrocerebral inactivity, performed in the absence of sedation, hypothermia, or major metabolic disorders, would be significantly modified after a 4-hour observation period; however the test needs to be performed at a distance from the initial condition that led to the clinical diagnosis of brain death. The need to repeat the EEG test, when the latter has been performed at an appropriate distance from the initial event, could be challenged. We recommend that further studies be conducted to evaluate the changes in EEG recording between two repeat tests. The goal would be to avoid the 4-hour inter-examination observation period, which can sometimes limit the use of EEG in certain situations, and can delay organ harvesting. While further studies are awaited to clarify these issues, we recommend repeating the EEG test while respecting an inter-examination observation period of at least 4 hours between both tests (measured from the beginning time of each EEG).
Medication The question of drug plasma levels for sedative drugs administered to the patient is an important and difficult issue, and is not mentioned in the French regulatory text of 1996. Some drugs, such as barbiturates, can have a long clearance level according to the drug’s half-life, and as such it is not always possible to wait for drug plasma levels to return to zero. The American Academy of Neurology (2005) stipulates: ‘‘If intoxicants such as barbiturates, benzodiazepines, or opioids are present, levels need not be zero, but should be in a range that would not normally be expected to interfere significantly with consciousness’’. Other scientific societies, and especially the Biomedicine Agency in its latest report on removing donated organs recommends simply that drug plasma levels be below therapeutic range. Techniques based on cerebral blood flow, not being influenced by sedative drugs, are recommended rather than EEG in this context. Furthermore, the study of evoked potentials (auditory and somatosensory) is an electrophysiological technique less sensitive to sedative drugs and hypothermia and could help determine the absence of cortical and sub-cortical activity, even though it has no medical-legal value in France today [12]. When it is impossible to use these alternative ancillary exams, it is preferable to wait for drug plasma levels results to come back before interpreting the EEG and wait for these levels to be validated as not interfering in a significant manner in cerebral electrogenesis.
Specificities for the diagnosis of brain death in children In France, there is no specific regulatory text for the diagnosis of brain death in children. However experts agree that adult criteria cannot be applied to young children [22].
103 The American Academy of Pediatrics (AAP) recently (2011) published its guidelines [17]. In the United States, the diagnosis of brain death is made solely on clinical criteria and the apnea test. ‘‘Ancillary studies (electroencephalogram and radionuclide cerebral blood flow) are not required to establish brain death and are not a substitute for the neurologic examination. However ancillary studies may be used to assist the clinician in making the diagnosis of brain death (i) when components of the examination or apnea testing cannot be completed safely due to the underlying medical condition of the patient; (ii) if there is uncertainty about the results of the neurologic examination; (iii) if a medication effect may be present; or (iv) to reduce the interexamination observation period’’. Experts all agree that the younger the child the longer the inter-examination observation period should be between the clinical examinations leading to the diagnosis of brain death: AAP recommends an observation period of 24 hours for term newborns (37 weeks gestational age) to 30 days of age, and 12 hours for infants and children (> 30 days to 18 years). Performing an ancillary exam (for example EEG) can reduce this observation period. Thus, the Société Franc ¸aise d’Anesthésie Réanimation published its guidelines in 2005 [3]: • ‘‘in children, the diagnosis of brain death is based on different criteria than in adults, after having excluded, just like in adults, confounding factors [3]; • in preterm newborns and term newborns under 7 days of life, because of cerebral immaturity, EEG is not a reliable indicator of brain death, and physicians should usually rely on cerebral angiography; • between the age of 7 days and 2 months, it is recommended to perform two clinical examinations and 2 EEGs with an inter-examination observation period of 48 hours, except in cases of anoxic brain injury; • between the age of 2 months and 1 year, it is recommended to perform two clinical examinations and 2 EEGs with an inter-examination observation period of 24 hours, except in cases of anoxic brain injury; • beyond the age of 1 year, criteria are similar to those applied to adults.’’ Some studies [2] suggest that there is no evidence to justify using different observation periods in adults and children above the age of 1 month. As a matter of fact, there are no reported cases of children who recovered neurological functions after having met all the criteria of brain death applied to adults [17]. A review of the literature based on 12 studies (published in the guidelines of the American Academy of Pediatrics in 2011) [17], on a cohort of 485 children suspected of brain death, is reported in these guidelines. It evaluated the sensitivity of EEG at 76% in children; this sensitivity increased to 89% with a repeat EEG test. Two false-positive tests were reported each time children were being given barbiturates. The sensitivity of EEG was as good as cerebral CT-angiography in children over the age of 1 month, but it was lower in the group of children under the age of 1 month (40% vs. 63%). Based on these data, we have established the following guidelines:
104 • the clinical examination and specific brain death criteria must be noted on the EEG request and must be repeated; • in preterm newborns and term newborns < 7 days of life, because of cerebral immaturity, EEG is not a reliable indicator of brain death, and it is recommended to use cerebral CT-angiography; • between the age of 7 days and 1 month, it is recommended to perform two EEG tests, respecting a 48-hour interexamination observation period; • between 1 month and 1 year: the recommended interexamination observation period is 24 hours; • above the age of 1 year: the recommended interexamination observation period is identical to that of adults. However these recommendations on age and observation periods are based on empirical knowledge, and we recommend conducting further studies to provide evidence-based data, in order to better refine ages and observation periods. In the specific context of infants, the interpreting physician must be experienced in neonatal EEG.
Conclusion EEG is a test used to validate brain death as listed in regulatory texts, adding evidence to the clinical criteria of brain death, but in no circumstance can it be a substitute to these clinical criteria. Two EEG recordings, respecting a 4-hour inter-examination observation period, are necessary. In this situation, electrocerebral inactivity is considered when EEG during a 30-minute, good quality recording evidences electrical inactivity defined as the absence of cerebral activity above 2 V, excluding the possible influence of sedation, metabolic disorders or hypothermia. In case of impregnation by sedative drugs, cerebral CTangiography will be the examination of choice. Criteria for the diagnosis of brain death in newborns and infants still need to be better clarified.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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