Detection of brain death onset using the bispectral index in severely comatose patients

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1 Intensive Care Med (2002) 28: DOI /s ORIGINAL Benoit Vivien Xavier Paqueron Philippe Le Cosquer Olivier Langeron Pierre Coriat Bruno Riou Detection of brain death onset using the bispectral index in severely comatose patients Received: 10 September 2001 Accepted: 2 January 2002 Published online: 19 March 2002 Springer-Verlag 2002 B. Vivien ( ) X. Paqueron P. Le Cosquer O. Langeron P. Coriat B. Riou Département d Anesthésie-Réanimation, Groupe Hospitalier Pitié Salpêtrière, Boulevard de l Hôpital, Paris, France benoit.vivien@psl.ap-hop-paris.fr Tel.: Fax: B. Riou Service d Accueil des Urgences, Groupe Hospitalier Pitié Salpêtrière, Paris, France Abstract Objectives: To evaluate the accuracy of bispectral index (BIS) monitoring for the diagnosis of brain death in severely comatose patients. Design: A prospective study in an intensive care unit of a university hospital. Population: Fifty-six severely comatose patients (Glasgow Coma Score 5) admitted to the ICU mainly because of intracerebral hemorrhage, head injury, or postanoxic coma. Methods: BIS was recorded continuously during the hospitalization in the ICU. Where necessary, clinical brain death was confirmed by EEG or cerebral angiography. Measurements and results: Twelve patients were already clinically brain dead at the time of admission, and their individual BIS values were 0. In each of these 12 patients brain death was thereafter confirmed by EEG or cerebral angiography. Fortyfour patients were not clinically brain-dead at the time of admission, and their individual BIS values were between 20 and 79. Twenty-seven of these patients became brain-dead, and their individual BIS values dropped to 0 in a few hours to a few days. In these 27 patients EEG or cerebral angiography was performed after the BIS value decreased to 0 and confirmed brain death in all cases. Seventeen patients who did not become brain dead during their hospitalization in the ICU had persistent electrocerebral activity on EEG, and their average BIS values remained above 35. Conclusion: BIS can be used in severely comatose patients as an assessment of brain death onset, enabling appropriate scheduling of either EEG or cerebral angiography to confirm brain death. Keywords Bispectral index Brain death Introduction When brain death is clinically suspected, investigations such as electroencephalography (EEG) and cerebral angiography are often mandatory, and are even required by law in some countries, to definitely confirm the diagnosis [1]. Nevertheless, the time of brain death is sometimes clinically difficult to determine precisely [2]. On the one hand, performing EEG or cerebral angiography before this is of little value. On the other hand, performing these investigations presents several drawbacks, as each is expensive because of the need for specialized personnel and technology. In addition, to perform cerebral angiography the patient must be transported out of the intensive care unit (ICU), with major medical risks, and the use of contrast media can be detrimental for the already compromised organs, such as kidneys [3]. For several years the bispectral index (BIS), a parameter derived from the EEG, has been reported as a quantifiable measure of the depth of sedation and degree of awareness during and after general anesthesia [4] and the depth of sedation in ICU [5, 6]. Good correlations have been reported between BIS and neurological status in unsedated coma patients [7, 8]. It has also been recently

2 420 suggested that BIS, in association with the Glasgow Coma Score (GCS), could be a good predictor of outcome after head trauma [9]. However, BIS monitoring during progression to brain death has been reported only anecdotally [10, 11]. Therefore we investigated the accuracy of BIS monitoring for the diagnosis of brain death in severely comatose patients. Patients and methods Study population The study was approved by our local ethics committee (CCPPRB, GH Pitié-Salpêtrière, Paris). Fifty-six consecutive patients were investigated prospectively over a 1-year period (Table 1). All of them had been admitted to the ICU for severe coma (GCS 5) resulting mainly from spontaneous intracranial hemorrhage, head injury, or cerebral anoxia. The cause of coma was established for every patient. Reversible abnormalities (drug and metabolic intoxications, hypothermia and shock) were excluded as the causes of coma. Because of the severity of their cerebral lesions at the time of admission into the ICU, all of these patients were potentially expected to progress to brain death. Care of the patients conformed to standard procedures in our ICU for severely comatose patients, with the additional use of the noninvasive BIS monitoring for studied patients. The skin was carefully cleaned before positioning the BIS sensor, which was covered by a self-adhesive plastic film. Each BIS sensor was used for a maximum of 72 h; nevertheless, in profusely sweating patients we sometimes had to change the BIS sensor every 24 h. We observed no skin breakdown after multiday recording. No patient was excluded from the study because his forehead was totally unavailable for positioning the BIS sensor. Data collection Demographic characteristics, cause of the coma, GCS, and neurological examination at the time of admission were recorded. Outcome was recorded as one of the following: already brain dead on admission to the ICU, progression to brain death, death from an extracerebral lesion, and alive at the time of discharge from the ICU. Two periods were considered for the accuracy of BIS to detect brain death: (a) initially, at the time of admission to the ICU, and (b) at the time of death or discharge from the ICU. For each assessment patients were classified in two groups: those who at the initial assessment were brain dead (BD Ini ) and those who were not braindead (NBD Ini ), and those who at the final assessment were braindead (BD Fin ) and those who were not brain-dead (NBD Fin ). BIS monitoring BIS and electromyographic (EMG) activity were recorded continuously using an A-2000 monitor (Aspect MS, Leiden, The Netherlands). Data were transferred and stored on a computer for off-line analysis. Since it has been shown that many devices such as cardiac pacing [12], forced-air warming systems [13], and radiofrequency noise in circumstances of extreme EEG suppression [14] can interfere with BIS monitoring, all of these artifacts were systematically noted and removed from computer file recordings during off-line analysis. Similarly, physical examination and care of the patient were carefully noted, since these could markedly interfere with BIS value either by neurological stimulation of the patient or by the production of artifacts. Definition of brain death Clinical diagnosis of brain death was defined as: (a) absence of hypothermia (<35 ) and drugs known to depress the central nervous system; (b) neurological examination demonstrating the absence of brainstem reflexes; (c) absence of spontaneous ventilation movement after 20 min of apnea, associated with an arterial PCO 2 higher than 60 mmhg. According to French law, the confirmatory test of brain death was: (d) no electrical activity over a 30-min period of EEG recording with maximal amplification during two consecutive examinations with at least 4 hours elapsed between the two recordings, or (e) absence of intracerebral blood flow on four-vessel cerebral angiography. Statistical analysis Data are expressed as mean ±SD. Sensitivity, specificity, and positive and negative predictive values were defined for the accuracy of BIS to detect brain death and were calculated by cumulating both initial and final evaluations (112 assessments in 56 patients). When the proportion was 100%, the 95% confidence interval was calculated as previously reported [15]. Results Progression to brain death Twelve patients were already clinically brain dead at the time of admission to the ICU (BD Ini ), and their individual BIS values remained permanently 0 (Fig. 1a). In each Table 1 Clinical features of the 56 severely comatose patients Cerebral pathology n Number of brain death Initially Intracerebral and/or subarachnoidal hemorrhage Brain-stem hemorrhage Head injury (blunt head trauma) Cerebral gunshot injury Cerebral anoxia (after cardiac arrest) Cerebral ischemia (carotid embolism) Cerebral air embolism Meningitis Total Finally

3 421 of these 12 patients brain death was then confirmed either by EEG (n=7) or by cerebral angiography (n=5). The 44 other patients were not clinically brain dead at the time of admission (NBD Ini ), and their individual BIS values were between 20 and 79. During a period of a few hours to a few days (29±31 h) 27 of these patients progressed to brain death, and their individual BIS values dropped to 0. In most of these cases brain death occurred less than 24 h after admission to the ICU (minimal time 2.5 h; Fig. 1b). However, in some patients whose neurological status was apparently stabilized brain death onset occurred only several days after admission to the ICU (maximal time 115 h). In these cases the decrease in BIS was a particularly useful signal of brain death, especially when clinical changes in neurological status were minimal. For 26 of these 27 patients who clinically evolved to brain death after admission to the ICU either EEG (n=24) or cerebral angiography (n=2) was performed after the BIS value decreased to 0 and confirmed brain death in all cases. Clinical diagnosis of brain death could not be confirmed in the 27th patient (cerebral gunshot injury) because cardiac arrest occurred before any EEG recording; nevertheless, since this patient fulfilled all clinical criteria of brain death, he was classified as BD Fin for the final assessment. Elsewhere, in one clinically braindead patient whose BIS values were still between 3 and 5, simultaneous EEG recording was not strictly isoelectric, showing a residual cortical activity; 12 h later the BIS values of this patient dropped to 0, and brain death was confirmed by two successive isoelectric EEG recordings. The total number of brain-dead patients at the end of the study (BD Fin ) was therefore 39. Finally, 17 patients who did not develop brain death during their hospitalization in ICU (NBD Fin ) had persistent activity on EEG, and their average BIS values remained above 35 (Fig. 1c). Among these 17 patients who did not progress to brain death, 9 died from extracerebral lesions, and 8 partially recovered and were transferred to a specialized neurological ICU. A summary of the course in the 56 patients is shown in Fig. 2. Fig. 1a c Typical bispectral index (BIS) and electromyographic activity (EMG) course in severely comatose patients. a BIS and EMG trend recordings in a 52-year-old brain-dead patient admitted to the ICU for organ donation. Before these recordings brain death was previously assessed by clinical examination and confirmed by cerebral angiography in another hospital. After family authorization this patient was transferred into our ICU for organ donation. As expected, upon arrival at the ICU the patient s BIS was permanently equal to 0, except some very small increases due to environmental activity. The regular peaks in EMG activity (vertical lines every 10 min) are linked to regular resets of the monitor for EMG monitoring. No sedative drugs were used in this patient. b BIS and EMG course in a 53-year-old patient admitted to the ICU after spontaneous intracerebral hemorrhage. Approximately 2.5 h after admission the BIS value dropped to 0 within a few minutes, simultaneously with clinical brain death and a slow decrease in EMG activity. Sedative drugs were stopped as soon as neurological examination worsened. Two EEG performed 1 and 5 h later confirmed brain death, and the patient s family allowed organ donation. c BIS and EMG course in a 46-year-old patient admitted to the ICU after spontaneous brainstem hemorrhage, with an initial GCS of 3. Sedative drugs were used in this patient for adaptation to ventilatory support. The BIS course showed slow variations according to level of sedation during the 20 h of recording. This patient partially recovered from his cerebral hemorrhage and was transferred 4 days later into a specialized neurological ICU

4 422 Fig. 2 Summary of the course of the 56 severely comatose patients studied Table 2 Overall accuracy of BIS monitoring to detect brain death. The overall number of evaluations for each group (brain dead and not brain dead) was calculated by cumulating both initial (n=56) and final (n=56) evaluations BIS=0 BIS>0 Total Brain dead Not brain dead Total During progression to brain death the BIS sometimes decreased to 0 a short time before complete clinical brain death. For example, in two patients, although the BIS value had already dropped to 0 within a few minutes, the cough response to bronchial suctioning was still present; in less than 2 h it finally disappeared, enabling the clinical diagnosis of brain death, which was thereafter confirmed by EEG. The overall accuracy of BIS monitoring to detect brain death was calculated by cumulating both initial (n=56) and final (n=56) evaluations (Table 2). Therefore sensitivity, specificity, and positive and negative predictive values were all equal to 100%. The 95% confidence interval for sensitivity and specificity=100% was calculated as [15]. Limitations of BIS monitoring Transient false positives The BIS value in one severely head injured patient transiently decreased from 40 to 0 for a few minutes on the third day after admission to the ICU while the oculocardiac reflex disappeared, and jugular venous saturation markedly decreased (Fig. 3). After intravenous infusion of mannitol the BIS returned to previous values as the oculocardiac reflex reappeared, and jugular venous saturation increased. Thereafter this patient never approached brain death during hospitalization in the ICU but died from multiple organ failure 6 days later. Transient false negatives In some of our 39 clinically brain-dead patients, either before or after confirmation of brain death by EEG or cerebral angiography, the BIS values sometimes increased for a few minutes, and afterwards decreased again to 0. These increases, sometimes reaching a BIS value of 90, were accompanied by simultaneous increases in EMG activity recorded on the BIS monitor (Fig. 4a). Elsewhere, in a few cases (5 of the 39 brain-dead patients), BIS increased from 0 and remained stable at a high level (up to 98) for a few hours. Again, in clinically braindead patients these increases were associated with simultaneous increases in EMG activity recorded on the BIS monitor. After intravenous administration of muscle relaxants the BIS quickly decreased again to 0 whereas EMG activity was considerably reduced (Fig. 4b). These overestimations of BIS because of important EMG activity were not specific to brain death. Indeed, in severely comatose patients who never approached brain death the administration of muscle relaxants was associated with a significant decrease in BIS values during the period of the paralysis; about 60 min later, as muscular paralysis

5 423 Fig. 3 Bispectral index (BIS) and electromyographic activity (EMG) course in a 34-year-old patient admitted to the ICU after severe blunt head trauma. On day 3 after admission the BIS value rapidly decreased to 0 during the night, while jugular venous oxygen saturation (SjvO 2 ) decreased and oculocardiac reflex disappeared. After intravenous administration of mannitol the BIS value increased again to previous values, while SjvO 2 increased and oculocardiac reflex reappeared disappeared, both BIS and EMG activity increased to previous values. Finally, in one patient whose brain death was certified by both clinical examination and cerebral angiography BIS values increased from 0 to an average of 60 (Fig. 4c). After myorelaxant injection BIS values did not decrease to 0 but only to 38 and remained fairly stable around this level. This hemodynamically unstable patient showed an important cardiovascular hyperpulsatility under epinephrine, responsible for head and neck move- Fig. 4a c Bispectral index (BIS) and electromyographic activity (EMG) trend recordings in patients for whom BIS values were overestimated. a BIS and EMG course in a 46-year-old patient admitted to the ICU About 4 h after admission to the ICU, BIS decreased to 0, whereas clinical examination suggested brain death onset. An EEG was immediately performed (time 100 min) and confirmed brain death. Approximately 30 min later, spontaneously, while no body and no device were in contact with the patient, EMG progressively increased, accompanied by significant increases in the BIS value. The increase in EMG signal was probably linked to brain death (enhancement of EMG activity in braindead patients) but was interpreted by the BIS monitor as EEG because of the absence of true EEG signal. b BIS and EMG course in a 58-year-old brain-dead patient admitted to the ICU for organ donation. Although brain death was confirmed by both clinical examination and cerebral angiography, BIS spontaneously increased to 98, associated with an important EMG activity, while no body and no device were in contact to the patient. After intravenous injection of myorelaxant the EMG activity was dramatically reduced in about 3 min, while BIS simultaneously dropped to 0. Afterwards BIS showed some small increases linked to patient care and physical examination. About 1 h later both signals recovered to previous values, as the effect of myorelaxant disappeared. c BIS and EMG course in a 50-year-old brain-dead patient admitted to the ICU after head injury. Although brain death was already certified by both clinical examination and cerebral angiography, BIS values increased from 0 to an average level of 50. Surprisingly, after myorelaxant injection the BIS values decreased not to 0 but only to 38, and remained stable around this level. On the other hand, after changing from epinephrine for norepinephrine to reduce cardiovascular important hyperpulsatility the BIS values quickly decreased to 0

6 424 ments, and the real-time EEG waveform displayed regular oscillations at the same frequency as heart rate. To reduce this hyperpulsatility epinephrine was changed for norepinephrine. Immediately after this switch the hyperpulsatility decreased, and the real-time EEG waveform oscillations disappeared, while BIS values quickly decreased to 0. No other overestimation of BIS values only due to cardiovascular hyperpulsatility was observed in the 38 remaining brain-dead patients. Discussion This study shows that in the 56 severely comatose patients studied BIS values were 0 in patients already brain-dead at the time of admission, and always decreased to 0 in the 37 patients who approached brain death during hospitalization in ICU. Against this, average BIS values remained above 35 in the 17 patients who never progressed to brain death during their hospitalization in ICU, and who had persistent electrocortical activity detected by EEG. Nevertheless, two important limitations of this monitoring were observed: (a) BIS could decrease to 0 before complete onset on brain death in patients with major intracranial hypertension, and (b) important EMG activity and cardiovascular hyperpulsatility could falsely elevate the BIS. In three patients the BIS decreased to 0 although these patients were not clinically brain dead. In one of them this decrease was accompanied by a worsening of neurological status, which required administration of an antiedematous treatment for correction. In the two other patients the BIS decreased to 0 a short time (1 or 2 h) before all the criteria of brain death were fulfilled. Nevertheless, according to the major cerebral injuries of these two patients, these decreases were interpreted as signal of impending brain death, allowing the scheduling of EEG or angiography and meeting with patients families. Therefore continuous BIS monitoring in severely comatose patients seems to be a very useful method for early detection of neurological worsening. In our ICU, this is particularly true for patients who have been hospitalized for several days in ICU, and whose neurological status is apparently stabilized, but who may be expected to deteriorate because of their cerebral injuries. Thus a decrease in BIS values, for example, during the night, is sometimes the first signal of such a deterioration. Indeed, good correlations between the BIS and neurological status have been reported in unsedated ICU patients and in neurosurgical ICU patients [8, 16]. Moreover, for refractory intracranial hypertension, Riker et al. [17] successfully used the BIS to titrate pentobarbital infusions. EMG activity is undoubtedly the main pitfall of BIS monitoring in severely comatose patients. While EEG and EMG signals are conventionally considered to remain in the bands of Hz and Hz, respectively, BIS uses EEG signals up to 47 Hz [18]. Indeed, clinically, low-frequency EMG activity has already been reported to falsely elevate BIS values in anesthetized patients without muscle relaxants [19]. Significant EMG activity may be present in brain-dead patients [20], and has been reported as a major artifact during EEG recordings for determining electrocortical silence [21, 22, 23]. Elsewhere, Mayr et al. [23], who reported tetaniform muscle activity during EEG recording in five potential organ donors, suggested that this enhanced EMG activity could be due to hyperexcitability of the nerve membrane caused by artificial hyperventilation in brain-dead patients. This interference between BIS and EMG activity is an important pitfall for using BIS in severely comatose and brain-dead patients. We hypothesize that this mistake is due in such patients to the very weak, or absence of, EEG signal, as compared to the EMG activity. In these cases the BIS monitor interprets EMG signals in the 30- to 47-Hz band as EEG, especially when there is no EEG signal in the Hz band. Similarly, Mychaskiw et al. [14] have reported a case of falsely elevated BIS during deep hypothermic circulatory arrest and propose that in such circumstances of extreme EEG suppression electrical interferences from either EMG or radiofrequency noise might be interpreted by the algorithm as EEG activity and assigned a high BIS value. This interference between EEG and EMG is also a major pitfall for EEG recording, especially in brain-dead patients for whom EMG activity may be enhanced [21, 22, 23]. Indeed, the administration of muscle relaxants is generally necessary in brain-dead patients to obtain reliable isoelectric EEG recordings [20, 21]. In our clinical practice we always consider EMG activity in interpreting BIS values in severely comatose patients. Therefore, if necessary, we recommend the administration of muscle relaxants when high EMG activity could interfere with BIS monitoring. In our opinion, this enables BIS to become a reliable means for monitoring EEG activity in severely comatose patients, especially when they are expected to progress to neurological worsening. Nevertheless, it should be kept in mind that this interference between EEG and EMG during BIS monitoring is not specific to severely comatose and brain-dead patients but has been previously reported to falsely elevate BIS values in anesthetized patients without muscle relaxants [19]. Indeed, EMG activity is not specifically a pitfall for BIS monitoring, having been described 20 years ago as a frequent contaminant of the EEG signal during general anesthesia [24]. The results presented here should be interpreted with caution. BIS monitoring in severely comatose patients is a new concept [7, 8, 9], far from the initial purpose of this monitor, and therefore new algorithms of analysis of bispectral index should probably be developed for such cases, especially in cases of very low EEG activity. Nonetheless, BIS seems to be an interesting monitoring

7 425 technique in severely comatose patients suffering from cerebral injuries. Indeed, the decrease in BIS to 0 might be used as an assessment of brain death onset, facilitating appropriate timing for either EEG or cerebral angiography to confirm brain death. On the one hand, performing these examinations too early, before actual brain death, is of limited value. Moreover, they should not be repeated since they are expensive and, at least regarding cerebral angiography, potentially deleterious. Against this, brain death is characterized by a major hemodynamic instability [2, 25], which is detrimental to the patient s organs. This instability is one important limit to organ donation, leading sometimes to a sudden and irreversible cardiac arrest, which prevents any organ donation [26]. Therefore the diagnosis of brain death should be made required as soon as possible. In conclusion, the decrease in BIS to 0 in severely comatose patients could be used as an assessment of brain death onset, enabling scheduling of appropriate timing for either EEG or cerebral angiography to confirm brain death. Nevertheless, further studies are needed to determine whether BIS, which is a simple noninvasive monitoring of EEG, can improve the timely diagnosis of brain death and therefore facilitate organ procurement for transplantation. Acknowledgements The writers are indebted to Dr. D.J. Baker, (Département d Anesthésie-Réanimation, Hôpital Necker, Paris, France), for reviewing the present manuscript. References 1. Wijdicks EF (2001) The diagnosis of brain death. N Engl J Med 344: Baillard C, Vivien B, Jasson S, Mansier P, Oubenaissa A, Riou B, Swynghedauw B (2000) Brain death assessment using instant spectral analysis of heart rate variability. Crit Care Med 30: Paolin A, Manuali A, Di Paola F, Boccaletto F, Caputo P, Zanata R, Bardin GP, Simini G. 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