今日の臨床サポート

脳死状態

著者: 園生雅弘1) 帝京大学 脳神経内科

著者: 宮地洋輔2) 横浜市立大学大学院医学研究科 神経内科学・脳卒中医学

監修: 永山正雄 国際医療福祉大学大学院医学研究科 脳神経内科学

著者校正済:2022/07/20
現在監修レビュー中
患者向け説明資料

概要・推奨   

  1. 患者の治療中に、法に規定する脳死判定を行ったとしたならば、脳死とされ得る状態の臨床徴候を認めたとき、担当医師等はその正確な診断に努める。
  1. 下記の①~④の検査を1回行い、それらの項目のすべてが満たされる場合に脳死とされ得る状態と判断する。
  1. ①深昏睡
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
園生雅弘 : 特に申告事項無し[2022年]
宮地洋輔 : 特に申告事項無し[2022年]
監修:永山正雄 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 定期レビューを行った(変更なし)。

まとめ

まとめ  
  1. 脳死(全脳死)は、「脳幹を含む脳全体のすべての機能が不可逆的に停止した状態」と定義される。これは器質的脳障害により深昏睡および無呼吸を来し、人工呼吸器が装着された症例の一部で起こる。いったん脳死に陥れば、いかに他臓器の保護手段をとっても通常1~2週間の内に心停止に至り、決して回復することはないとされる。
  1. 脳死判定は日本においては「臓器の移植に関する法律」(以下「臓器移植法」)によって定義されており、臓器移植を前提とするときにこれが適用される。これを法的脳死判定という。それ以外の場面における医学的な脳死判定においてもこれは参考となる。
  1. 具体的な法的脳死判定の方法としては、法的脳死判定マニュアルに従うべきである。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
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文献 

Abstract/Text Based on the findings in a collaborative study of 503 comatose and apneic patients, the establishment of cerebral death requires (1) that all appropriate examinations and therapeutic procedures have been performed, (2) that cerebral unresponsivity, apnea, dilated pupils, absent cephalic reflexes, and electrocerebral silence be present for 30 minutes at least six hours after the ictus, and (3) that if one of these standards is met imprecisely or cannot be tested, a confirmatory test be made to demonstrate the absence of cerebral blood flow. This would allow the diagnosis of a dead brain to be made in patients with small amounts of sedative drugs in the blood, In patients undergoing therapeutic procedures that make examination of one or more of the cranial nerves impossible, and in patients otherwise meeting the criteria whose pupils are small.

PMID 576252
C Pallis
ABC of brain stem death. Reappraising death.
Br Med J (Clin Res Ed). 1982 Nov 13;285(6352):1409-12.
Abstract/Text
PMID 6814579
Eelco F M Wijdicks, Panayiotis N Varelas, Gary S Gronseth, David M Greer, American Academy of Neurology
Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology.
Neurology. 2010 Jun 8;74(23):1911-8. doi: 10.1212/WNL.0b013e3181e242a8.
Abstract/Text OBJECTIVE: To provide an update of the 1995 American Academy of Neurology guideline with regard to the following questions: Are there patients who fulfill the clinical criteria of brain death who recover neurologic function? What is an adequate observation period to ensure that cessation of neurologic function is permanent? Are complex motor movements that falsely suggest retained brain function sometimes observed in brain death? What is the comparative safety of techniques for determining apnea? Are there new ancillary tests that accurately identify patients with brain death?
METHODS: A systematic literature search was conducted and included a review of MEDLINE and EMBASE from January 1996 to May 2009. Studies were limited to adults.
RESULTS AND RECOMMENDATIONS: In adults, there are no published reports of recovery of neurologic function after a diagnosis of brain death using the criteria reviewed in the 1995 American Academy of Neurology practice parameter. Complex-spontaneous motor movements and false-positive triggering of the ventilator may occur in patients who are brain dead. There is insufficient evidence to determine the minimally acceptable observation period to ensure that neurologic functions have ceased irreversibly. Apneic oxygenation diffusion to determine apnea is safe, but there is insufficient evidence to determine the comparative safety of techniques used for apnea testing. There is insufficient evidence to determine if newer ancillary tests accurately confirm the cessation of function of the entire brain.

PMID 20530327
Eelco F M Wijdicks, Alejandro A Rabinstein, Edward M Manno, John D Atkinson
Pronouncing brain death: Contemporary practice and safety of the apnea test.
Neurology. 2008 Oct 14;71(16):1240-4. doi: 10.1212/01.wnl.0000327612.69106.4c.
Abstract/Text BACKGROUND: Little is known of hospital practice in brain death determination, specialty involvement, and followed procedures, including the apnea test.
METHODS: We reviewed 228 patients pronounced brain dead at Mayo Clinic from 1996 to 2007. We performed a detailed review of clinical determination of brain death, intensive care support, apnea test procedure, and complications.
RESULTS: There were 228 patients who were pronounced brain dead, mostly after traumatic brain injury, cerebral hematoma, or aneurysmal subarachnoid hemorrhage. Brain death was declared within 24 hours of ictus in 30% of the patients and within 3 days in 62%. All patients were using one or more vasopressors, and 61% of the patients received vasopressin for diabetes insipidus. An apnea test could not be performed in 7% of the patients because of hemodynamic instability or poor oxygenation at baseline. In 3% of the patients, the apnea test procedure was aborted because of hypoxemia or hypotension. No major complications (cardiac arrest or pneumothorax) occurred during the apnea test. Polytrauma resulting in brain death was significantly more common in patients with aborted or not attempted apnea tests than in patients with completed apnea tests (p = 0.0004). During the study epoch, we found a shift toward determination of the tests by neurointensivists, pediatric neurologists, and neurosurgeons.
CONCLUSIONS: Brain death declaration is frequent within the first 3 days of admission. It is usually performed in hemodynamically unstable patients requiring vasopressors and vasopressin. If preconditions are met, apnea testing using an oxygen-diffusion technique is safe. However, in 1 of 10 patients, an apnea test could not be completed and confirmatory tests were needed.

PMID 18852438
Simon Lévesque, Martin R Lessard, Pierre C Nicole, Stéphan Langevin, François LeBlanc, François Lauzier, Jacques G Brochu
Efficacy of a T-piece system and a continuous positive airway pressure system for apnea testing in the diagnosis of brain death.
Crit Care Med. 2006 Aug;34(8):2213-6. doi: 10.1097/01.CCM.0000215114.46127.DA.
Abstract/Text OBJECTIVE: To prospectively compare three methods of apnea testing for the confirmation of brain death.
DESIGN: Prospective, randomized, crossover study.
SETTING: Intensive care unit of a tertiary care university hospital.
PATIENTS: Twenty adult patients requiring apnea testing for confirmation of brain death.
INTERVENTIONS: Ten minute apnea testing was repeated in random order for every patient with the three oxygenation systems: oxygen catheter inserted through the endotracheal tube (oxygen 6 L/min), T-piece system (oxygen 12 L/min), and continuous positive airway pressure (CPAP) system 10 cm H2O (oxygen 12 L/min).
MEASUREMENTS AND MAIN RESULTS: Arterial blood was drawn at 0, 2, 5, and 10 mins of each test. Compared with baseline, Paco2 increased by 30.6 +/- 7.4, 30.0 +/- 7.3 and 30.2 +/- 7.5 mm Hg during the apnea period (p = .96), reaching 73.3 +/- 8.3, 71.6 +/- 11.1, and 72.7 +/- 9.0 mm Hg at the end of the apnea test (p = .73) for the oxygen catheter, the T-piece, and the CPAP, respectively. Pao2 decreased less with the CPAP compared with the oxygen catheter or the T-piece (-22.4 +/- 76, -99.1 +/- 158, and -91.6 +/- 133 mm Hg, respectively, p < .01). In two patients, apnea testing could not be completed with the oxygen catheter and the T-piece because of desaturation, although it could be completed with the CPAP.
CONCLUSIONS: The T-piece and the CPAP systems are effective alternatives to the standard oxygen catheter technique for apnea testing. Oxygenation was best maintained with the CPAP system, which can be useful in some patients.

PMID 16540953
Benoît Vivien, Frédéric Marmion, Sabine Roche, Catherine Devilliers, Olivier Langeron, Pierre Coriat, Bruno Riou
An evaluation of transcutaneous carbon dioxide partial pressure monitoring during apnea testing in brain-dead patients.
Anesthesiology. 2006 Apr;104(4):701-7.
Abstract/Text BACKGROUND: Diagnosis of brain death usually requires an arterial carbon dioxide partial pressure (Paco2) of 60 mmHg during the apnea test, but the increase in Paco2 is unpredictable. The authors evaluated whether transcutaneous carbon dioxide partial pressure (Ptcco2) monitoring during apnea test can predict that a Paco2 of 60 mmHg has been reached.
METHODS: The authors compared Ptcco2 measured with a transcutaneous ear sensor (V-Sign Sensor, Sentec Digital Monitoring System; SENTEC-AG, Therwil, Switzerland) and Paco2 obtained from arterial blood gas measurements in 32 clinically brain-dead patients.
RESULTS: In the first 20 patients, the mean Paco2-Ptcco2 gradient was 0.7 +/- 3.6 mmHg at baseline and 8.7 +/- 7.1 mmHg after 20 min of apnea. Using receiver operating characteristic curve analysis (area under the curve: 0.983 +/- 0.013), the best threshold value of Ptcco2 to predict that a Paco2 of 60 mmHg had been reached was 60 mmHg (positive predictive value: 1.00 [0.93-1.00]). In the following 12 patients investigated with use of this Ptcco2 target value of 60 mmHg, the mean duration of the apnea test (11 +/- 4 vs. 20 +/- 0 min; P < 0.001), hypercapnia (74.0 +/- 4.9 vs. 98.3 +/- 20.0 mmHg; P < 0.001), acidosis (pH: 7.18 +/- 0.06 vs. 7.11 +/- 0.08; P < 0.001), and decrease in arterial oxygen partial pressure (-47 +/- 44 vs. -95 +/- 89; P < 0.05) at the end of the test were reduced as compared with the 20-min apnea test group.
CONCLUSION: During the apnea test in brain-dead patients, a Ptcco2 of 60 mmHg accurately predicts that a Paco2 of 60 mmHg has been reached. This may allow a reduction in the duration of the apnea test and consecutively limit occurrence of complications.

PMID 16571965
C J G Lang, J G Heckmann, F Erbguth, A Druschky, M Haslbeck, F Reinhardt, M Winterholler
Transcutaneous and intra-arterial blood gas monitoring--a comparison during apnoea testing for the determination of brain death.
Eur J Emerg Med. 2002 Mar;9(1):51-6.
Abstract/Text Intra-arterial (i.a.) and transcutaneous (t.c.) blood gas monitoring were compared with in vitro blood gas analysis (abg) during apnoea testing for the determination of brain death in a prospective observational study. All three methods were used simultaneously in 19 patients in whom brain death was suspected. Brain death was confirmed in each case adhering to the recommendations of the Scientific Advisory Board of the German Federal Chamber of Physicians which demand a PCO2 of at least 60 mmHg. In vitro parameters ranged from 23.2 to 80.4 mmHg (PCO2), 52.7 to 509.9 mmHg (PO2), and 7.072 to 7.591 (pH). The intra-individual correlations between both monitoring methods (rPCO2=0.958, rPO2=0.859) and between each of them and abg (r>0.960) were high. Absolute deviations from abg for the corrected as well as uncorrected measurements were similar for both methods, except with regard to group bias where an advantage for the i.a. values emerged. Since many of the i.a. measurements failed and the disposable i.a. probes cost much more than the t.c. electrodes, the i.a. technique at present holds no advantage over t.c. measurements in testing for apnoea in suspected brain death except where simultaneous monitoring of pH and temperature are desired.

PMID 11989498
Eelco F M Wijdicks, Edward M Manno, Steven R Holets
Ventilator self-cycling may falsely suggest patient effort during brain death determination.
Neurology. 2005 Sep 13;65(5):774. doi: 10.1212/01.wnl.0000174626.94197.62.
Abstract/Text
PMID 16157923
S M Willatts, G Drummond
Brainstem death and ventilator trigger settings.
Anaesthesia. 2000 Jul;55(7):676-7.
Abstract/Text A patient with cerebral infarction was certified clinically brainstem dead. However, 4 h after the diagnosis of death, while the patient was being ventilated using the biphasic positive airway pressure mode, the 'assist' indicator light on the Drager Evita 2 ventilator illuminated intermittently. There was no evidence of spontaneous breathing. 'Triggering' was probably caused by a decrease in airway pressure in time with cardiac contraction. The trigger flow rate is crucial as factors other than the patient's inspiratory effort can initiate flow from the ventilator with very sensitive settings.

PMID 10919424
Gustavo Saposnik, Vincenzo S Basile, G Bryan Young
Movements in brain death: a systematic review.
Can J Neurol Sci. 2009 Mar;36(2):154-60.
Abstract/Text Brain death is the irreversible lost of function of the brain including the brainstem. The presence of spontaneous or reflex movements constitutes a challenge for the neurological determination of death. We reviewed historical aspects and practical implications of the presence of spontaneous or reflex movements in individuals with brain death and postulated pathophysiological mechanisms. We identified and reviewed 131 articles on movements in individuals with confirmed diagnosis of brain death using Medline from January 1960 until December 2007, using 'brain death' or 'cerebral death' and 'movements' or 'spinal reflex' as search terms. There was no previous systematic review of the literature on this topic. Plantar withdrawal responses, muscle stretch reflexes, abdominal contractions, Lazarus's sign, respiratory-like movements, among others were described. For the most part, these movements have been considered to be spinal reflexes. These movements are present in as many as 40-50% of heart-beating cadavers. Although limited information is available on the determinants and pathophysiological mechanisms of spinal reflexes, clinicians and health care providers should be aware of them and that they do not preclude the diagnosis of brain death or organ transplantation.

PMID 19378707
W D Goldie, K H Chiappa, R R Young, E B Brooks
Brainstem auditory and short-latency somatosensory evoked responses in brain death.
Neurology. 1981 Mar;31(3):248-56.
Abstract/Text Thirty-five patients who met all clinical criteria for brain death and 53 patients who did not were tested with brainstem auditory (BAER) and short-latency somatosensory (SER) evoked responses. Of the brain-dead patients, 77% had no waves present in the BAER, including wave I, whereas 69% had medullary components present in the SER. These data suggest that the SER has greater clinical utility in the brain-death setting, because it is important to have a wave present that established that the input signal has reached the central nervous system. No brain-dead patients had subsequent waves in either test. These results are correlated with neuropathologic findings and contrasted with data obtained in the comatose but not brain-dead patients.

PMID 7193818
A R Møller, P Jannetta, M Bennett, M B Møller
Intracranially recorded responses from the human auditory nerve: new insights into the origin of brain stem evoked potentials (BSEPs).
Electroencephalogr Clin Neurophysiol. 1981 Jul;52(1):18-27.
Abstract/Text Auditory evoked potentials were recorded intracranially from the 8th nerve during neurosurgical procedures. The potentials had a large negative peak that occurred 3.0--3.7 msec after the onset of the stimulus (2 000 Hz tone bursts). When these potentials were compared with the scalp recorded brain stem evoked potentials (BSEPs) the intracranial response was found to match the latencies of the P2N3 complex of the BSEP. The results are interpreted as showing that the neural generator of the second peak of the BSEP is the intracranial portion of the auditory nerve and not, as was earlier assumed, the cochlear nucleus.

PMID 6166449
G Saposnik, J A Bueri, J Mauriño, R Saizar, N S Garretto
Spontaneous and reflex movements in brain death.
Neurology. 2000 Jan 11;54(1):221-3.
Abstract/Text Spontaneous and reflex movements may be found in patients with brain death (BD). The authors prospectively evaluated their frequency using a standardized protocol. Among 38 patients who fulfilled criteria for BD, the authors found 15 (39%) with spontaneous or reflex movements. The most common movement was finger jerks. Undulating toe flexion sign, triple flexion response, Lazarus sign, pronation-extension reflex, and facial myokymia also were seen. These movements may be more common than reported and do not preclude the diagnosis of BD.

PMID 10636153
J F Spittler, D Wortmann, M von Düring, W Gehlen
Phenomenological diversity of spinal reflexes in brain death.
Eur J Neurol. 2000 May;7(3):315-21.
Abstract/Text In brain death, spinal reflexes and automatisms are observed which may cause irritation and even doubt in the diagnosis. In the literature there are no dedicated descriptions of the diversity and of neuroanatomical considerations. In 278 examinations of 235 patients for the determination of brain death, on 42 occasions obvious spinal reflexes and/or spinal automatisms were observed in 27 brain dead bodies. Because they were not systematically searched for, minute forms have probably been missed. The reflexes (R) and automatisms (A) are described according to the time of observation in relation to the development of brain death, the presumable spinal localization and the possible phylogenetical interpretation. Especially disquieting examples are discussed in more detail, e.g. monophasic EndotrachealSuction-ThoracicContraction-R supposedly switched in segments C2-6 or TrapeziusPinch-ShoulderProtrusion-R conveyed by the accessory nerve (terminology according to the scheme: for the reflexes, Trigger-Response-R: for the automatisms, Movement-A). After these experiences a more thorough examination showed frequent observations of rather minute forms of spinal reflexes, as well as automatisms and even the Lazarus sign (in possibly more than two thirds of the examinations). An estimation of the factual frequency would necessitate special attention to those much more frequent but less obvious minute spinal reflexes and automatisms.

PMID 10886316
Gustavo Saposnik, Jorge Maurino, Roberto Saizar, José A Bueri
Spontaneous and reflex movements in 107 patients with brain death.
Am J Med. 2005 Mar;118(3):311-4. doi: 10.1016/j.amjmed.2004.09.013.
Abstract/Text
PMID 15745731
J Santamaria, N Orteu, A Iranzo, E Tolosa
Eye opening in brain death.
J Neurol. 1999 Aug;246(8):720-2.
Abstract/Text
PMID 10460452
Maria Leticia C Araullo, Jeffrey I Frank, Fernando D Goldenberg, Axel J Rosengart
Transient bilateral finger tremor after brain death.
Neurology. 2007 Apr 17;68(16):E22. doi: 10.1212/01.wnl.0000260227.36359.18.
Abstract/Text
PMID 17438210
K-Y Jung, S-G Han, K H Lee, C-S Chung
Repetitive leg movements mimicking periodic leg movement during sleep in a brain-dead patient.
Eur J Neurol. 2006 Jul;13(7):e3-4. doi: 10.1111/j.1468-1331.2006.01270.x.
Abstract/Text
PMID 16834692
Manoj K Mittal, Grace M Arteaga, Eelco F M Wijdicks
Thumbs up sign in brain death.
Neurocrit Care. 2012 Oct;17(2):265-7. doi: 10.1007/s12028-012-9729-6.
Abstract/Text INTRODUCTION: Spinal reflexes can be seen in the setting of brain death. We present a new spinal reflex. We also review spinal movements in pediatric brain death and provide suggestions to distinguish them from movements generated by the brain.
CASE REPORT: We report a five-year old girl admitted after an asystolic cardiac arrest and was soon declared brain death as a result of bilateral cerebellar hematoma. She had spinal movements including a "Thumbs up sign". These findings delayed organ procurement.
CONCLUSION: "Thumbs up sign" should be added to the list of spinal reflexes seen with brain death. Spinal reflexes in brain death can be clinically recognized and should explained to all involved parties to avoid unnecessary testing, confusion for family members, and delay or refusal of organ donation.

PMID 22772839
Abstract/Text
PMID 3700636
A S Wee
Scalp EMG in brain death electroencephalogram.
Acta Neurol Scand. 1986 Aug;74(2):128-31.
Abstract/Text Electromyograms (EMGs) are usually considered artifacts during electroencephalographic (EEG) recording for determination of electrocerebral silence (ECS). Appearance of scalp motor unit activity, however, may reflect residual brainstem function and can introduce difficulty in establishing a secure diagnosis of brain death. In this study, ECS patients with and without scalp EMG were compared in terms of relationship to brainstem survivability. There was no correlation between length of survivability and presence of scalp EMG activity. No patient recovered brainstem function clinically. This study provides firm support for the usual practice of ignoring the EMG in brain death EEG. Scalp has no prognostic value.

PMID 3776460
M Sonoo, Y Tsai-Shozawa, M Aoki, T Nakatani, Y Hatanaka, A Mochizuki, M Sawada, K Kobayashi, T Shimizu
N18 in median somatosensory evoked potentials: a new indicator of medullary function useful for the diagnosis of brain death.
J Neurol Neurosurg Psychiatry. 1999 Sep;67(3):374-8.
Abstract/Text OBJECTIVES: To record N18 in median somatosensory evoked potentials (SEPs) for deeply comatose or brain dead patients and to demonstrate the usefulness of N18 for the diagnosis of brain death in comparison with auditory brain stem responses (ABRs) and P13/14 in median SEPs, which have been conventionally used as complementary tests for the diagnosis of brain death.
METHODS: Subjects were 19 deeply comatose or brain dead patients. Thirteen recordings were performed in deeply comatose but not brain dead conditions, and 12 recordings were performed in brain death. N18 was evaluated in the CPi-C2S lead (or other scalp-C2S leads) to obtain a flat baseline.
RESULTS: N18 was preserved in 12 of 13 non-brain dead comatose recordings whereas it was completely lost for all of the 12 brain death recordings. P13/14 in median SEPs was preserved for all the comatose recordings, whereas apparent P13/14-like potentials, usually of low amplitude, were seen in nine of 12 brain death recordings-that is, frequent false positives. The ABRs already showed features which were characteristic for brain death (loss of components other than wave 1 or small wave 2) for four comatose recordings, in three of which N18 was preserved. The last result not only corresponds with the fact that ABRs can evaluate pontine and midbrain functions and not medullary function, but further supports the medullary origin of N18. In the four patients followed up for the course of progression from coma to brain death, N18s preserved in normal size during the comatose state were completely lost after brain death was established.
CONCLUSIONS: The N18 potential is generated by the cuneate nucleus in the medulla oblongata in the preceding studies. N18 is suggested to be a promising tool for the diagnosis of brain death because there were no false positives and rare false negatives in the present series for detecting the remaining brain stem function.

PMID 10449562
Enrico Facco, M Munari, F Gallo, S M Volpin, A U Behr, F Baratto, G P Giron
Role of short latency evoked potentials in the diagnosis of brain death.
Clin Neurophysiol. 2002 Nov;113(11):1855-66.
Abstract/Text OBJECTIVE: The aim of this study is to confirm the effectiveness of auditory brain-stem responses (ABRs) and somatosensory evoked potentials (SEPs) in the diagnosis of brain death (BD).
METHODS: ABRs and SEPs were recorded at the same session in 130 BD patients (age range 8-77 years, 81 male and 49 female). Twenty-four cases were submitted to serial recordings from preterminal conditions through BD.
RESULTS: ABRs were absent in 92 cases (70.8%), only waves I or I-II were present in 32 cases (24.6%), while in the remaining 6 patients (4.6%) waves V and/or III were still present, excluding the death of the brain-stem. In 4 cases (3.1%) SEPs showed the absence of all components following the cervical N9, preventing the diagnosis of BD. Among 126 cases (96.9%) with preserved cervical N9-N13 SEPs confirmed the absence of brain-stem activity in 122 cases (93.7%), in whom no waves following P11 or P13 were recordable. SEPs excluded the diagnosis of BD in the remaining 4 cases (3.2%) showing preserved P14 and/or N18. In all pre terminal patients the far-field P14-N18 were present, and their disappearance was closely related to the onset of BD.
CONCLUSIONS: The combined us of ABRs and SEPs was able to confirm BD in almost all patients, providing an objective confirmation of the diagnosis, and to exclude it in 7 cases, thus improving the reliability of diagnosis.

PMID 12417241
Christophe Quesnel, Jean-Pierre Fulgencio, Christophe Adrie, Béatrice Marro, Laurent Payen, Nadège Lembert, Sonia El Metaoua, Francis Bonnet
Limitations of computed tomographic angiography in the diagnosis of brain death.
Intensive Care Med. 2007 Dec;33(12):2129-35. doi: 10.1007/s00134-007-0789-6. Epub 2007 Jul 21.
Abstract/Text OBJECTIVE: To evaluate the accuracy of cerebral computed tomographic angiography (CT-a) for the diagnosis of brain death (BD).
DESIGN AND SETTING: Prospective observational study in intensive care units.
PATIENTS: Twenty-one clinically BD patients enrolled over 12 months.
MEASUREMENTS AND RESULTS: All clinically BD patients were evaluated by electroencephalography (EEG) and CT-a after exclusion of hypothermia and drug intoxication. Data collected included: demographic characteristics, cause of BD, delay between in-hospital admission and BD diagnosis and between EEG and CT-a, occurrence of cardiac arrest, administration of vasoactive agents, results of EEG and CT-a. We evaluated the sensitivity of EEG and CT-a and their agreement. Groups were compared according to BD diagnosis by EEG and CT-a (E+C+), or only by EEG (E+C(-)). Statistical analysis were performed by Mann-Whitney test and Fisher's exact test. BD was confirmed by EEG in all cases (sensitivity 100%) whereas only 11 patients of 21 had no cerebral perfusion during CT-a (sensitivity 52.4%). No agreement was documented between EEG and CT-a for the diagnosis of BD (kappa = 0). Patients' characteristics did not differ between E+C+ and E+C(-) groups. In the E+C(-) group arterial opacification was observed in 100% of patients, but opacification of the internal cerebral veins was achieved in only 30%.
CONCLUSIONS: In clinically BD patients with no electroencephalographic activity CT-a documents opacification of the intracerebral vessels in a significant percentage of the cases. Therefore CT-a cannot be recommended as a means of BD diagnosis.

PMID 17643226
J-C Combes, A Chomel, F Ricolfi, P d'Athis, M Freysz
Reliability of computed tomographic angiography in the diagnosis of brain death.
Transplant Proc. 2007 Jan-Feb;39(1):16-20. doi: 10.1016/j.transproceed.2006.10.204.
Abstract/Text OBJECTIVE: This study examined the validity of cerebral computed tomographic (CT) angiography in the diagnosis of brain death (BD) compared with conventional cerebral angiography.
METHODS: This prospective, monocentric study was performed over a 24-month period and included 43 patients, at least 18 years of age, with clinical criteria of BD. All patients underwent cerebral CT angiography and then cerebral angiography. To confirm BD, the CT scan had to show the absence of perfusion of A2 anterior cerebral artery segments (A2-ACA), M4 middle cerebral artery segments (M4-MCA), P2 posterior cerebral artery segments (P2-PCA), basilar artery, internal cerebral veins, and finally the great cerebral vein. Cerebral angiography showed cerebral blood flow arrest at the level of the foramen magnum for posterior circulation and carotid siphon for anterior circulation.
RESULTS: For 30 patients, BD was confirmed by both examinations. For 13 patients, cerebral angiography confirmed BD, whereas CT angiography still showed cerebral perfusion; the divergence rate was 30.2%.
CONCLUSIONS: CT angiography seems to be a promising exam to confirm BD. However, the divergence with cerebral angiography is significant mainly concerning A2-ACA, which are proximal. It may be possible to only use the absence of opacification of M4-MCA, P2-PCA, basilar artery, and venous blood return to remain in conformity with the French law. In all cases, the international medical community should obtain a consensus for the interpretation of CT angiography to use it extensively as a complementary exam for BD.

PMID 17275466
Tim Taylor, Rob A Dineen, Dale C Gardiner, Charmaine H Buss, Allan Howatson, Nathan Leon Pace
Computed tomography (CT) angiography for confirmation of the clinical diagnosis of brain death.
Cochrane Database Syst Rev. 2014 Mar 31;3:CD009694. doi: 10.1002/14651858.CD009694.pub2. Epub 2014 Mar 31.
Abstract/Text BACKGROUND: The diagnosis of death using neurological criteria (brain death) has profound social, legal and ethical implications. The diagnosis can be made using standard clinical tests examining for brain function, but in some patient populations and in some countries additional tests may be required. Computed tomography (CT) angiography, which is currently in wide clinical use, has been identified as one such test.
OBJECTIVES: To assess from the current literature the sensitivity of CT cerebral angiography as an additional confirmatory test for diagnosing death using neurological criteria, following satisfaction of clinical neurological criteria for brain death.
SEARCH METHODS: We performed comprehensive literature searches to identify studies that would assess the diagnostic accuracy of CT angiography (the index test) in cohorts of adult patients, using the diagnosis of brain death according to neurological criteria as the target condition. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5) and the following databases from January 1992 to August 2012: MEDLINE; EMBASE; BNI; CINAHL; ISI Web of Science; BioMed Central. We also conducted searches in regional electronic bibliographic databases and subject-specific databases (MEDION; IndMed; African Index Medicus). A search was also conducted in Google Scholar where we reviewed the first 100 results only. We handsearched reference lists and conference proceedings to identify primary studies and review articles. Abstracts were identified by two authors. Methodological assessment of studies using the QUADAS-2 tool and further data extraction for re-analysis were performed by three authors.
SELECTION CRITERIA: We included in this review all large case series and cohort studies that compared the results of CT angiography with the diagnosis of brain death according to neurological criteria. Uniquely, the reference standard was the same as the target condition in this review.
DATA COLLECTION AND ANALYSIS: We reviewed all included studies for methodological quality according to the QUADAS-2 criteria. We encountered significant heterogeneity in methods used to interpret CT angiography studies and therefore, where possible, we re-analysed the published data to conform to a standard radiological interpretation model. The majority of studies (with one exception) were not designed to include patients who were not brain dead, and therefore overall specificity was not estimable as part of a meta-analysis. Sensitivity, confidence and prediction intervals were calculated for both as-published data and as re-analysed to a standardized interpretation model.
MAIN RESULTS: Ten studies were found including 366 patients in total. We included eight studies in the as-published data analysis, comprising 337 patients . The methodological quality of the studies was overall satisfactory, however there was potential for introduction of significant bias in several specific areas relating to performance of the index test and to the timing of index versus reference tests. Results demonstrated a sensitivity estimate of 0.84 (95% confidence interval (CI) 0.69 to 0.93). The 95% approximate prediction interval was very wide (0.34 to 0.98). Data in three studies were available as a four-vessel interpretation model and the data could be re-analysed to a four-vessel interpretation model in a further five studies, comprising 314 patient events. Results demonstrated a similar sensitivity estimate of 0.85 (95% CI 0.77 to 0.91) but with an improved 95% approximate prediction interval (0.56 to 0.96).
AUTHORS' CONCLUSIONS: The available evidence cannot support the use of CT angiography as a mandatory test, or as a complete replacement for neurological testing, in the management pathway of patients who are suspected to be clinically brain dead. CT angiography may be useful as a confirmatory or add-on test following a clinical diagnosis of death, assuming that clinicians are aware of the relatively low overall sensitivity. Consensus on a standard radiological interpretation protocol for future published studies would facilitate further meta-analysis.

PMID 24683063
Andreas H Kramer, Derek J Roberts
Computed tomography angiography in the diagnosis of brain death: a systematic review and meta-analysis.
Neurocrit Care. 2014 Dec;21(3):539-50. doi: 10.1007/s12028-014-9997-4.
Abstract/Text BACKGROUND: Physiological instability and confounding factors may interfere with the clinical diagnosis of brain death. Computed tomography angiography (CTA) has been suggested as a potential ancillary test for confirmation of brain death, but its diagnostic accuracy remains unclear.
METHODS: We searched MEDLINE, EMBASE, and CENTRAL for studies comparing CTA with other accepted methods of diagnosing brain death (clinical or radiographic). Summary estimates of diagnostic accuracy were computed using random effects models. Subgroup analyses and meta-regression were performed to assess associations between CTA sensitivity and study or patient characteristics.
RESULTS: Twelve studies, involving 541 patients, were included. If the CTA criterion for brain death was complete lack of opacification of intracranial vessels, then the pooled sensitivity was 62 % (50-74 %) for venous phase and 84 % (75-94 %) for arterial phase imaging. The sensitivity of CTA was higher when the criterion for brain death involved absence of opacification of internal cerebral veins, either alone (99 %, 97-100 %) or in combination with lack of flow to the distal middle cerebral artery branches (85 %, 77-93 %). CTA sensitivity was not influenced by different reference standards (clinical vs. radiographic) or predominant diagnostic category (stroke vs. brain trauma). Specificity of CTA could not be adequately determined from the existing data.
CONCLUSION: Many patients who progress to brain death by accepted clinical or radiographic criteria have persistent opacification of proximal intracranial vessels when CTA is performed. The specificity of CTA in the diagnosis of brain death has not been adequately assessed. Routine use of CTA as an ancillary test in the diagnosis of brain death is therefore not recommended until diagnostic criteria have undergone further refinement and prospective validation. Absence of opacification of the internal cerebral veins appears to be the most promising angiographic criterion.

PMID 24939056
Louisa M Monteiro, Casper W Bollen, Alexander C van Huffelen, Rob G A Ackerstaff, Nicolaas J G Jansen, Adrianus J van Vught
Transcranial Doppler ultrasonography to confirm brain death: a meta-analysis.
Intensive Care Med. 2006 Dec;32(12):1937-44. doi: 10.1007/s00134-006-0353-9. Epub 2006 Sep 21.
Abstract/Text OBJECTIVE: Barbiturate therapy or hypothermia precludes proper diagnosis of brain death either clinically or by EEG. Specific intracranial flow patterns indicating cerebral circulatory arrest (CCA) can be visualized by transcranial Doppler ultrasonography (TCD). The aim of this study was to assess the validity of TCD in confirming brain death.
DESIGN: Meta-analysis of studies assessing the validity of TCD in confirming brain death.
METHODS: A systematic review of articles in English on the diagnosis brain death by TCD, published between 1980 and 2004, was performed. An oscillating or reverberating flow and systolic spikes were considered to be compatible with CCA. The quality of each study was assessed using standardized methodological criteria. The literature was searched for any article reporting a false-positive result.
RESULTS: Two high-quality and eight low-quality studies were included. Meta-analysis of the two high-quality studies showed a sensitivity of 95% (95% CI 92-97%) and a specificity of 99% (95% CI 97-100%) to detect brain death. Meta-analysis of all ten studies showed a sensitivity of 89% and a specificity of 99%. In the literature we found two false-positive results; however, in both patients brain-stem function did show brain death shortly thereafter.
CONCLUSIONS: CCA by TCD in the anterior and posterior circulation predicted fatal brain damage in all patients; therefore, TCD can be used to determine the appropriate moment for angiography. Further research is needed to demonstrate that CCA by TCD on repeated examination can also predict brain death in all patients.

PMID 17019556
A H Karantanas, G M Hadjigeorgiou, K Paterakis, D Sfiras, A Komnos
Contribution of MRI and MR angiography in early diagnosis of brain death.
Eur Radiol. 2002 Nov;12(11):2710-6. doi: 10.1007/s00330-002-1336-z. Epub 2002 Apr 17.
Abstract/Text The objective of this study was to investigate whether the findings of MR imaging and MR angiography could accurately and early diagnose brain death in comatose patients. Thirty comatose patients were studied with MRI and MR arteriography. In 20 patients (group A) presenting with a Glasgow coma scale (GCS) 3-6, the final clinical diagnosis was brain death. In ten comatose patients with a GCS 4-6 and no clinical signs of brain death (group B), the clinical follow-up did not reveal brain death in a period of 12 months. The MRI examination consisted of turbo fluid-attenuated inversion recovery and T2 turbo spin-echo pulse sequences. The MR arteriography was performed with a 3D inflow pulse sequence. In 12 patients with brain death and 5 patients with no signs of brain death, a 3D phase contrast MR venography was also applied. Magnetic resonance imaging in all patients showed variable edema with swelling of the cerebral gyri, small ventricular system, and basilar subarachnoid spaces. In group A, MRI in addition showed tonsillar herniation. In group A, MR arteriography revealed no arterial flow in the intracranial circulation, whereas MR venography showed in 9 patients no opacification of the sagittal and straight sinuses or visualization of intracranial veins. In contrast, MR angiography showed intact intracranial vessels in patients of group B. In conclusion, MR imaging and MR angiography may be reliable ancillary tests for use in early diagnosis of brain death and further work is required to validate its utility.

PMID 12386761
K Ishii, T Onuma, T Kinoshita, G Shiina, M Kameyama, Y Shimosegawa
Brain death: MR and MR angiography.
AJNR Am J Neuroradiol. 1996 Apr;17(4):731-5.
Abstract/Text SUMMARY: Four patients in whom brain deaths was identified on the basis of neurologic and electroencephalographic findings were examined with MR imaging and MR angiography. MR images showed diffuse swelling of the cerebral gyri and cerebellar cortex, which prolongation of both the T1 and T2 signal (representing hypoxic ischemic brain injury), downward displacement of the diencephalon and the brain stem (central and tonsillar herniation), and loss of flow void in the intracranial portions of both internal carotid arteries. MR angiograms did not show the intracranial vessels above the level of the supraclinoid portion of the internal carotid arteries. MR angiography and MR imaging are noninvasive and reliable methods for use in determining brain death.

PMID 8730194
A Matsumura, K Meguro, H Tsurushima, Y Komatsu, Y Kikuchi, M Wada, Y Nakata, N Ohashi, T Nose
Magnetic resonance imaging of brain death.
Neurol Med Chir (Tokyo). 1996 Mar;36(3):166-71.
Abstract/Text Fifteen patients with clinical diagnosis of brain death were examined by magnetic resonance (MR) imaging. Aortography with intraarterial digital subtraction angiography (IADSA) was also performed in nine patients. MR imaging indications of the flow void phenomenon were evaluated in the cavernous portion of internal carotid artery (ICA) and the middle or anterior cerebral artery, and compared with the IADSA findings. The relative intensities of gray and white matters were also measured. MR imaging showed that flow voids were absent in the ICA in all eight patients in whom non-filling was confirmed by IADSA. In one patient, IADSA demonstrated intracranial flow despite the diagnosis of brain death and the flow void pattern was normal. Serial MR imaging showed disappearance or abnormality of flow voids after brain death in six patients and absence before brain death in one. Spotty flow voids became visible in the unilateral ICA of one case after brain death. Partial residual flow voids may be caused by to-and-fro blood movement which was demonstrated by transcranial Doppler sonography. The normal flow void pattern was seen in none of these patients, therefore absence of flow voids indicates cessation of intracranial blood flow. Proton density and T2-weighted MR images showed dissociated intensity changes between white and gray matters, which were thought to be characteristic of brain death. In conclusion, MR imaging can achieve non-invasive diagnosis of the non-filling phenomenon in patients with brain death.

PMID 8869153
K O Lövblad, C Bassetti, C Basssetti
Diffusion-weighted magnetic resonance imaging in brain death.
Stroke. 2000 Feb;31(2):539-42.
Abstract/Text UNLABELLED: BACKGROUND; Traditionally the diagnosis of brain death is established on the basis of a combination of clinical signs and paraclinical methods. Diffusion-weighted MRI is a new method sensitive to cerebral ischemia. Its value in brain death has not been demonstrated until now.
CASE DESCRIPTION: A patient was referred to MRI with suspicion of a brain stem stroke. Echo-planar whole-brain, multislice, diffusion-weighted MRI was performed in addition to conventional sequences and MR angiography sequences. In addition to the extensive bilateral hyperintensities observed on T2-weighted images, diffusion-weighted MRI showed diffuse hyperintensities involving both hemispheres as well as a severe drop in the apparent diffusion coefficient in both affected hemispheres. There was also transtentorial herniation with compression of the brain stem as well as absence of flow voids on the T2-weighted images and absence of intracranial vessels on MR angiography. On the basis of the clinical and imaging findings, it was concluded that the patient was in a state of brain death. The patient died the same day.
CONCLUSIONS: With the use of new fast techniques such as diffusion-weighted imaging, now MRI can not only display anatomic changes associated with severe brain suffering but can also demonstrate ultrastructural changes secondary to brain death and differentiate them from edematous changes seen on T2-weighted images.

PMID 10657434
Kevin J Donohoe, Garima Agrawal, Kirk A Frey, Victor H Gerbaudo, Giuliano Mariani, James S Nagel, Barry L Shulkin, Michael G Stabin, Margaret K Stokes
SNM practice guideline for brain death scintigraphy 2.0.
J Nucl Med Technol. 2012 Sep;40(3):198-203. doi: 10.2967/jnmt.112.105130. Epub 2012 Jun 28.
Abstract/Text
PMID 22743146
Marina Munari, Pietro Zucchetta, Carla Carollo, Franco Gallo, Marco De Nardin, Maria Cristina Marzola, Stefano Ferretti, Enrico Facco
Confirmatory tests in the diagnosis of brain death: comparison between SPECT and contrast angiography.
Crit Care Med. 2005 Sep;33(9):2068-73.
Abstract/Text OBJECTIVE: Cerebral blood flow tests have increasingly been advocated for the confirmation of brain death (BD). Four-vessel angiography has been considered the most reliable investigation in the diagnosis of BD for >30 yrs, but it is invasive. (99m)Tc-HMPAO SPECT provides noninvasive, multiplanar imaging of brain tissue perfusion. The aim of this study was to check the reliability of SPECT compared with contrast angiography.
DESIGN: Prospective, blind study.
SETTING: Neurointensive care unit of a university hospital.
PATIENTS: Consecutive clinically brain dead patients with flat electroencephalogram.
INTERVENTIONS: BD was diagnosed according to Italian law. (99m)Tc-HMPAO SPECT and four-vessel angiography were performed in the same session; the rater of each investigation ignored the results of the other. Blood pressure, Sp(O2), and P(ECO2) were monitored throughout the study: any episode of hypoxia or hypotension caused exclusion of the patient from the study.
MEASUREMENTS AND MAIN RESULTS: Twenty brain dead patients were enrolled. The cause of BD was head injury in seven cases (35%), subarachnoid hemorrhage in seven (30%), spontaneous hemorrhage in one (10%), brain tumors in two (10%), stroke in two (10%), and thrombosis of the sagittal sinus in one (5%). Both angiography and SPECT confirmed BD in 19 of 20 patients: angiography showed the absence of filling of intracranial arteries, while SPECT showed a picture of "empty skull." For the remaining patient, angiography showed slight and late filling of left vertebral, basilar, and posterior cerebral arteries, while SPECT showed faint traces of uptake in the posterior fossa on the right side and on the midline. For this patient, the tests were repeated 48 hrs later, and both showed the arrest of intracranial circulation, thus confirming BD.
CONCLUSIONS: Our results confirm the reliability of SPECT in the diagnosis of BD; because SPECT is noninvasive, it is a good candidate for the "gold standard" of diagnosis.

PMID 16148482
W P Dillon, R V Lee, M J Tronolone, S Buckwald, R J Foote
Life support and maternal death during pregnancy.
JAMA. 1982 Sep 3;248(9):1089-91.
Abstract/Text
PMID 7109202
Christopher M Burkle, Jennifer Tessmer-Tuck, Eelco F Wijdicks
Medical, legal, and ethical challenges associated with pregnancy and catastrophic brain injury.
Int J Gynaecol Obstet. 2015 Jun;129(3):276-80. doi: 10.1016/j.ijgo.2014.12.011. Epub 2015 Mar 3.
Abstract/Text In late 2013, two women from North America gained attention after sustaining catastrophic brain injuries while pregnant. After Marlise Muñoz--who was at 14 weeks of pregnancy when she developed a pulmonary embolism--was pronounced brain dead, hospital officials initially refused to withdraw support, citing a Texas state law requiring them to maintain life-sustaining treatment for a pregnant patient to help to save the fetus. By contrast, when Robyn Benson was pronounced brain dead after a brain hemorrhage at 22 weeks of pregnancy, both her husband and the physicians agreed to continue support until a viable child could be delivered. The Muñoz and Benson cases offer an opportunity to explore the medical, legal, and ethical issues surrounding catastrophic brain injury in pregnant women. It is hoped that the present article will enable clinicians to better appreciate the history and present state of issues involving advance directives for pregnant women, maternal versus fetal interests, and the impact of fetal viability on medical decision making, as well as offer a practical assessment of the various US state laws concerning the rare, yet catastrophic event of brain injury in a pregnant woman.

Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
PMID 25754143
Majid Esmaeilzadeh, Christine Dictus, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Michael Eichbaum, Stefan Hofer, Guido Engelmann, Hamidreza Fonouni, Mohammad Golriz, Jan Schmidt, Andreas Unterberg, Arianeb Mehrabi, Rezvan Ahmadi
One life ends, another begins: Management of a brain-dead pregnant mother-A systematic review-.
BMC Med. 2010 Nov 18;8:74. doi: 10.1186/1741-7015-8-74. Epub 2010 Nov 18.
Abstract/Text BACKGROUND: An accident or a catastrophic disease may occasionally lead to brain death (BD) during pregnancy. Management of brain-dead pregnant patients needs to follow special strategies to support the mother in a way that she can deliver a viable and healthy child and, whenever possible, also be an organ donor. This review discusses the management of brain-dead mothers and gives an overview of recommendations concerning the organ supporting therapy.
METHODS: To obtain information on brain-dead pregnant women, we performed a systematic review of Medline, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). The collected data included the age of the mother, the cause of brain death, maternal medical complications, gestational age at BD, duration of extended life support, gestational age at delivery, indication of delivery, neonatal outcome, organ donation of the mothers and patient and graft outcome.
RESULTS: In our search of the literature, we found 30 cases reported between 1982 and 2010. A nontraumatic brain injury was the cause of BD in 26 of 30 mothers. The maternal mean age at the time of BD was 26.5 years. The mean gestational age at the time of BD and the mean gestational age at delivery were 22 and 29.5 weeks, respectively. Twelve viable infants were born and survived the neonatal period.
CONCLUSION: The management of a brain-dead pregnant woman requires a multidisciplinary team which should follow available standards, guidelines and recommendations both for a nontraumatic therapy of the fetus and for an organ-preserving treatment of the potential donor.

PMID 21087498

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