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BIS and INVOS monitoring: possibilities and limitations in neurosurgery

De Buysscher P., Veeckman L. M.D.


In neuroanaesthesia, we encounter two major challenges. First of all, anaesthesia can be defined as a state of drug-induced unconsciousness in which the patient neither perceives nor recalls noxious stimulation, so logically the depth of anaesthesia is one of the most important issues in neuroanaesthesia. On the other hand, monitoring the oxygenation of the cerebral blood flow is also of great importance, In the last decade, two types of monitoring devices have gained popularity in the daily practice of neuroanaesthesia. In Vivo Optical Spectroscopy (INVOS) and the Bispectral Index (BIS) are the two most used. Since they have a completely different application field, both will be discussed separately.

anaesthesia and the regional oxygen saturation of cerebral blood are the two most important factors of monitoring in neuroanaesthesia. In this review, we will evaluate the latest developments in the technology of two most popular types of brain monitoring devices, the In Vivo Optical Spectroscopy (INVOS) and the Bispectral Index Scale (BIS). Both have a completely different application field, the first one being used mainly to prevent ischaemic insults in the brain while the latter finds its use in monitoring the depth of anaesthesia. Using recent studies and reviews, we will evaluate the latest developments of both techniques, based on their individual possibilities and achievements in general anaesthesiology and their application in the field of neurosurgery, without losing sight of the problems these devices still pose in the daily practice considering the controversial outcome in certain leading studies.

Although the central nervous system (CNS) is the primary endpoint of most general anaesthetics, it is still the least monitored organ in clinical anaesthesiology, and anaesthesia is usually managed using indirect parameters of adequate brain oxygenation, such as heart rate, blood pressure, and peripheral oxygenation.1 CNS monitoring is technically difficult and demanding: moreover, anaesthetic drugs directly interfere with brain activity, increasing the objective difficulties of data interpretation. Most CNS monitors are designed to monitor cerebral hemodynamics or cerebral electrical activity. Monitors of cerebral hemodynamics include the measurement of intracranial pressure (ICP), cerebral blood flow velocity (TCD) and cerebral blood flow (CBF) using different techniques such as 133-Xenon, double-indicator dilution, positron emission tomography, laser Doppler flowmetry or transcranial Doppler ultrasonography. Monitors of electrical activity include electroencephalography (EEG), the somato-sensory evoked potentials

Anaesthesia can be defined as a state of drug-induced unconsciousness in which the patient neither perceives nor recalls noxious stimulation. Until recently, anaesthesiologists lacked the ability to monitor the effects of anaesthetics of the brain in terms of depth or adequacy of anaesthesia. Typically, surrogate measures of autonomic activity, such as changes in blood pressure and heart rate, have been used to assess the adequacy or inadequacy of anaesthesia. Anaesthesiologists also encounter difficulties monitoring the changes in the regional oxygen saturation of the blood in the brain. In the past decade, new monitoring devices have moved from the experimental stage to the operating theatre, all with the common goal to detect, as quickly as possible, intraoperative ischemic insults so that the brain and the spinal cord may be protected from harmful and frequently inevitable events due to the type of surgery, patient positioning, hemodynamic changes or any intercurrent event. Both issues, the depth of

(SSEPs), electrocorticography, electromyography and Bispectral Analysis (BIS). The last one will be discussed later on. However, none of these monitors provide information of the adequacy of brain tissue oxygenation. 2 Direct monitoring of brain oxygenation can be obtained by direct measurement of brain tissue oxygen tension (PtO2), or monitoring the jugular venous oxygen saturation (SjvO2). Both techniques have proven their usefulness in several studies and in the daily practice especially for patients with head injury, subarachnoid haemorrhage or intraoperatively during aneurysm surgery, but their advantages and downsides would take us too far and dont fall within the aim of this review. Also, these invasive monitoring systems may be associated with severe complications, and cannot be performed routinely in all anesthetized patients. Non-invasive monitoring is being rapidly integrated into our daily work because of its lack of secondary effects. 3-4 In the last decade, technological research has expanded the application of near-infrared spectroscopy (NIRS) to allow continuous, noninvasive, and bedside monitoring of regional cerebral oxygen saturation (rSO2) through the scalp and skull, providing accurate information on the balance between brain oxygen supply.5

INVOS technology
Most clinicians still regard the brain as a black box, and our ability to assess brain function in comatose patients is still limited. NIRS technology may offer a means of monitoring the brain in these patients who have complex conditions. The INVOS (In Vivo Optical Spectroscopy) system non-invasively and continuously monitors changes in the regional oxygen saturation (rSO2) of the blood in the brain. Changes in INVOS values monitor the critical balance between oxygen delivery and cerebral consumption. The INVOS Cerebral Oximeter measurement is made by non-invasively transmitting and detecting harmless, low intensity and near infrared light through sensors that are placed on both sides of a patient's forehead.6 The physical and mathematic basis for near-infrared spectroscopy (NIRS) is provided by the Beer-Lambert law, which states that a portion of the light transmitted through a solution containing a coloured compound is absorbed by the compound, with the result that the intensity of the emerging light is reduced.7 Light scatters in tissues; in the microcirculation, it is absorbed differently by oxygenated and deoxygenated haemoglobin. Our eyes see this difference when bright red oxygenated blood changes to deep bluish and blackish deoxygenated blood. NIRS measures the amount of

light returned to the sensor, producing a ratio of oxygenated haemoglobin to total haemoglobin (expressed as a percentage). So, NIRS is based on the different absorption characteristics of oxygenated and deoxygenated haemoglobin: oxygenated haemoglobin (HbO2) absorbs less red light (600-750 nm) and more infrared light (8501000 nm) than does deoxygenated haemoglobin (Hb). As a result, Hb has an absorption peak at 740 nm while HbO2 does not. Near infrared light photons are injected into the skin over the forehead. After being scattered about inside the scalp, skull, and brain, some fraction of the injected photons survive to return and exit the skin ("reflectance"). By measuring the quantity of returning photons as a function of wavelength, one can infer the spectral absorption of the underlying tissue and make certain conclusions about its average oxygenation. 8 A measurement within the cerebral tissues is allowed by the trans-illumination characteristics of the skull with near-infrared light. Since nearinfrared light penetrates all tissues included in the cranium, the differentiation between brain vasculature and the bone and soft tissues is obtained with spatial resolution. The rationale of spatial resolution is based on the finding that intracranial depth of photon penetration from an infrared source applied to the forehead skin is influenced by the distance of its separation from an adjacent detector: accordingly, by using a pair of detectors with differing separation from the infrared source, surface reflections can be subtracted from those coming from the brain tissues. In fact, the sensor incorporates a light source and two return signal detectors at different pre-determined distances from the light source. The signal detector nearest the light source (30 mm) is considered the shallow detector and the further detector from the light source (40 mm) the deep detector. (figure 1) By subtracting the shallow signal from the deep one, extracerebral signals are suppressed and the result is a measurement of predominantly cerebral haemoglobin oxygenation saturation.1

Figure 1: INVOS scheme illustrating the bananashaped double signal detection resulting from spatial dispersion

There are at the moment several cerebral oximeters actually available for clinical use. One of them is a saturation monitor INVOS4100 (Adult) and 5100 (Adult and Pediatric) (Somanetic Corporation, Troy, MI). This monitor uses a lightemitting diode transmitting near-infrared light at two wavelengths (735 and 810 nm), and two silicon photodiodes as light detectors. Both the light source and detectors are enclosed in a common adhesive strip assembly, which is applied to the patients forehead. The monitor thus provides a single numerical value for each hemisphere, representing the regional cerebral oxygen saturation (rSO2) measured in the cerebrovascular tissue under the sensor applied to the forehead skin.9,10 (Figure 2)

Application of INVOS in neurosurgery

Neurosurgical patients are at risk of cerebral ischemia because of the imbalance between oxygen supply and demand. Cerebral perfusion pressure is the physiologic variable suggesting the presence or absence of cerebral ischemia; but requires the placement of an invasive device to measure intracranial pressure (ICP). Transcranial cerebral oximetry is a non-invasive monitoring of cerebral oxygen saturation potentially providing accurate and online information on the metabolic balance between oxygen supply and demand of the brain. Initial use and development of NIRS technology actually started and was developed to implement monitoring of the brain in patients with neurosurgical problems, such as patients with vasospasm, stroke, or patients undergoing hypothermia and circulatory arrest for repair of complex cranial aneurysms.12 Because light in near-infrared wavelengths can penetrate skull and brain, transcranial monitoring is feasible with the NIRS device. There is great value in monitoring for signs of ischemia during neurovascular procedures. In most studies we encountered, NIRS was used to evaluate cerebral oxygenation during carotid surgery and during cardiac surgery, both on-bypass and off pump in order to avoid intraoperative ischemia. In a study of carotid endarterectomy, Kuroda and colleagues found that NIRS measurements identified severe cerebral hypoxia during clamping of the carotid artery.13 An American study from 2006 monitored 25 neurovascular procedures including aneurysm clip placement, arteriovenous malformation resection, carotid endarterectomy, superficial temporal artery-middle cerebral artery (MCA) bypass surgery, external carotid artery-MCA bypass surgery, encephaloduromyosynangiosis, and balloon occlusion testing using NIRS. Bilateral monitoring was performed in all cases. Five of the patients exhibited evidence of clinical ischemic events during the procedures. One patient suffered blood loss with systemic hypotension and developed diffuse brain oedema intraoperatively, one patient suffered an ischemic event intraoperatively and developed an occipital stroke postoperatively, and one patient showed slowing on electroencephalography intraoperatively during carotid clamping; in two patients balloon occlusion testing failed. In all cases of ischemic events occurring during the procedure, NIRS monitoring showed a decrease in HbO2 and SO2. 14 Dujovny et al described the use of rSO2 monitoring may prove to be especially advantageous in patients where blood circulation in the brain is already compromised. They used cerebral oximetry based on NIRS for non-invasive evaluation of the rSO2 to preoperatively assess

Figure 2: The INVOS monitor. The major difference between pulse oximeters and cerebral oximeters is that in pulse oximeters the transmission of near-infrared light is gated by the arterial pulse by means of a plethismographic reading, while in cerebral oximeters it is more or less continuous. Also, NIRS has greater tissue penetration than pulse oximetry. Pulse oximeters measure oxygen saturation of haemoglobin in arterial blood, while cerebral oximeters measure haemoglobin in the entire tissue bed, which includes a mixture of brain tissue, arterial, and venous blood. Since the ratio of arterial and venous blood is about 15:85, and it is not affected by hypoxia and hypocapnia, NIRS primarily measures cerebral venous saturation, reflecting the balance between oxygen supply and demand in the brain.11 On the other hand, the measurement can be affected by changes in blood oxygenation, cerebral blood flow, haemoglobin content and cerebral metabolic rate. Accordingly, the information provided by new cerebral oximeters can be used to identify cerebral oxygen imbalances and take corrective action, while once the cause of an oxygen imbalance is identified and therapy initiated, continuously monitoring cerebral oxygenation can provide immediate feedback regarding the adequacy of the selected therapy.

patients with skull base tumours and giant arterial aneurysms, for whom possible occlusion or partial resection of the internal carotid artery was considered. Monitoring cerebral oxygen saturation was performed during both endovascular (balloon) and open surgical test occlusions of the internal carotid artery. The presence (or absence) of changes in the cerebral oxygen saturation served as a criterion of the patient's tolerance to permanent occlusion of the internal carotid artery. In all cases the curves of saturation accurately corresponded to the clinical condition of the patients, primarily to the developing of neurological signs. 15 Dunham et al evaluated the correlation between cerebral oximetry and invasive determination of cerebral perfusion pressure (CPP), and reported that cerebral saturation correlated significantly with cerebral perfusion pressure and other clinically important variables in patients with severe traumatic brain injury, suggesting the use of this monitoring as a non-invasive and user-friendly measure of CPP. 16 Another important application of cerebral oximetry monitoring in neurosurgical patients is the detection and treatment of vascular vasospasm: Ekelund et al evaluated the correlation between cerebral oximetry and transcranial Doppler ultrasound velocity of basal cerebral artery in 14 patients undergoing surgery for aneurismal subarachnoid haemorrhage and reported a correlation between the two systems, supporting the idea that these non-invasive methods increase the reliability in detecting early changes in cerebral blood flow that might result in cerebral ischemia, potentially allowing an earlier treatment aimed at initiating cerebral protection. 17 Kashiwazaki et al report an interesting and unique use of NIRS during haemodialysis in a patient with right internal carotid artery occlusion. During a drop in blood pressure while on dialysis, the patients ipsilateral regional frontal oxygen saturation (rSO2) decreased from 52 to 37, a relative drop of 29%, whereas the contralateral side remained near baseline.18,19 This cerebral desaturation corresponded with a period of left hemiparesis that resolved with administration of noradrenalin to raise blood pressure. Subsequent right superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis improved cerebrovascular reserve, eliminated the symptoms of cerebral ischemia, and prevented a later rSO2 decline during a similar blood pressure drop during dialysis. Although this report describes only a single patient, it illustrates the potential benefits of NIRS to improve outcomes.

Limitations of INVOS:
The former cerebral oximeters had several limitations due to the lack of absolute chromophore

concentration measurements, mainly resulting in difficulties in determining baseline values, and very wide patient-to-patient variations in optical scattering characteristics. However, it has been shown that the majority of variation in path length across individuals is related to scattering in the extracranial tissue layers caused by variations in scalp, skull and cerebrospinal fluid later thickness. Since spatial resolution removes the signals originating in these extracranial layers, it is able to correct for differences in scattering and path length occurring in these layers. Due to the wide patient-to-patient variability of baseline rSO2 values in each patient, the baseline value should be determined before inducing general anaesthesia, and cerebral ischemia is related more to the changes from baseline than to the absolute value: a reduction of 20% from baseline is usually accepted as clinical threshold of cerebral ischemia. 20-21 Another limitation of the INVOS system we encountered is the limited depth of measurement in the brain tissue. The most likely measurable photon penetration depth is about a third of the spacing between the light source and the detector. So if we use a monitor in which the source and the detector are 40 mm apart, the average depth of measurement is about 13 mm into the target. Between the sensor where it contacts the skin and the cerebral cortex there are several layers of tissue of differing composition and with different concentrations of blood. We refer to this extracerebral tissue as simply "scalp and skull" or occasionally just "scalp." To reduce the interference of extracerebral oxygen on the oxygenation measurement, the INVOS system uses two sourcedetector spacings: a "near" (shallow) spacing of 3 cm and a "far" (deep) spacing of 4 cm. Both sample about equally the shallow layers in the tissue volumes directly under the light sources and detectors, but the far spacing "sees" deeper than the near spacing. Subtraction of some of the near signals from the far theoretically should leave a signal originating predominantly in the brain cortex. 22-23 Thavasothy et al made a comparison of cerebral oxygenation as measured by the NIRO 300 and the INVOS 5100 and they concluded that although both monitors might be usefully applied in the clinical setting, the large degree of intra- and intersubject variability makes their absolute values of uncertain clinical value. 24 Similar results were found by Yoshitani for the the INVOS 4100 and the NIRO 300 near-infrared spectrophotometers. 25 Yoshitani et al conducted a study in which they investigated the effect of a reduction in haemoglobin through haemodilution during surgery on cerebral oxygen saturation, comparing jugular venous bulb oxygen saturation (SjO2) and regional cerebral oxygen saturation (ScO2) using the

INVOS4100S. Their results indicated that ScO2 can decrease even during mild haemodilution and changes in ScO2 may differ from those in SjO2 during haemodilution. The changes in SjO2 and ScO2 values were not modified by the background anaesthetics used, although SjO2 values, but not ScO2 values, were significantly lower under propofol anaesthesia compared with those under sevoflurane/nitrous oxide anaesthesia. So, in clinical situations, the discrepancy between the results of SjO2 and ScO2 makes their interpretation difficult. Further studies will be necessary to clarify this point. 26 It remains unclear whether the information derived from the NIRS device provides an adequate sample of the brain so that areas of hypoperfusion can be detected. In addition, we require more investigations to determine whether monitoring brain tissue oxygenation is clinically relevant and can translate into therapeutic actions that will improve neurologic outcomes.

Anaesthesia can be defined as a state of drug-induced unconsciousness in which the patient neither perceives nor recalls noxious stimulation. A satisfactory anaesthetic state can be obtained by a balance of hypnotic drugs (e.g., volatile or intravenous anaesthetics) and analgesic drugs (e.g., opioids), resulting in unconsciousness, amnesia and areflexia. Generally, a balance between hypnosis and analgesia is sought. If the dose of hypnotic agent is large, then relatively smaller amounts of analgesic are needed. If analgesic doses are relatively large, then hypnotic medications are decreased to avoid hemodynamic instability. Until recently, anaesthesiologists lacked the ability to monitor the effects of anaesthetics of the brain in terms of depth or adequacy of anaesthesia. Typically, surrogate measures of autonomic activity, such as changes in blood pressure and heart rate, have been used to assess the adequacy or inadequacy of anaesthesia. In 1996, the USA Food and Drug Administration (FDA) approved an Electroencephalographic-based monitor using bispectral analysis, known as the Bispectral Index Scale (BIS). BIS is one of several systems used in anaesthesiology to measure the effects of specific anaesthetic drugs on the brain and to track changes in the patient's level of sedation or hypnosis. It was first developed in the early 1990s by applying bispectral analysis to EEG recordings.

Conventional analysis of the EEG using fast Fourier transformation produces information regarding the power, frequency and the phase of the EEG signal.1 Typical displays, such as the compressed spectral array, graph power and frequency information and discard the phase information.27 Bispectral analysis represents a different description of the EEG in that interfrequency phase relations are measured, i.e., the bispectrum quantifies the relations among the underlying sinusoidal components of the EEG. The data contained in both the bispectral analysis and conventional frequency-power analyses of the EEG are used to create the proprietary parameter of the BIS.27 In other words, bispectral analysis is a method of analyzing the mathematical relationships among the various components of an EEG signal (phase couplings) as well as measuring amplitudes and frequencies, so a computer inside an anaesthesia monitor is able to analyze data from a patient's EEG during surgery. To compile a database for the index, researchers recorded EEGs from several thousand patients and volunteers anesthetized with a range of commonly used anaesthetics and anaesthetic combinations. Each subject's depth of unconsciousness was evaluated on the basis of a modified version of the Observer's Assessment of Alertness/Sedation Scale (OAA/SS) (in the volunteers) or the amount of drug concentration in blood serum (in the patients). Segments of the recorded EEGs were used to draw up a set of EEG features that were then tested for their ability to distinguish between different levels of sedation or unconsciousness. The index that resulted from this process was then tested on different EEG recordings from the researchers' larger database. It is scaled from 100 to 0 so that the BIS value decreases linearly with increasing doses of anaesthesia.27,28 To understand the BIS as an EEG-derived variable, we have to first understand the fundamental EEG changes that occur with the deepening of propofol target-controlled infusion (TCI) or sevoflurane anaesthesia. EEG sedation measures have been developed based on the observation that the EEG generally changes from a low amplitude, high frequency signal while awake to a large amplitude, low frequency signal when deeply anaesthetized. During relaxation with the eyes closed, there is an (7.512.5 Hz) wave predominance. Light anaesthesia is accompanied by a decrease in the and an increase in (12.530 Hz) power. With deepening of anaesthesia, slow wave activity - namely (1.53.5 Hz) and (3.5 7.5 Hz) waves - increase and become more prominent, with a simultaneous decrease in the and activities in all regions. This represents a decrease in the cortical generator of and activities, with a shift toward control by the

thalamo-hippocampal-septal generators of and activities. All these changes are reversed in the same order with the return of consciousness.29 The BIS is a dimensionless number ranging from 100 (fully awake) to 0 (isoelectric EEG). The BIS is the weighted sum of three descriptors: Relative BetaRatio, a frequencydomain feature, is the EEG spectral power log (P30 47 Hz/P1120 Hz), SynchFastSlow, a bispectral-domain feature, is the bispectral power wave band log (B0.5 47 Hz/B4047 Hz), and Burst Suppression is a timedomain feature that quantifies the extent of isoelectrical silence. None of these descriptors is particular per se because each has a specific range of effect at which they perform best. BetaRatio is

the most influential during light hypnotic states; SynchFastSlow predominates during surgical levels of anaesthesia; and Burst Suppression detects very deep anaesthesia. The BIS analysis uses a proprietary algorithm that allows the different descriptors to sequentially dominate as the EEG changes character with increasing depth of anaesthesia.29,30 (Figure 3) Two studies 31,32 showed that it may be valid to measure BIS with the sensor on the occipital area instead of on the normal frontal area if required during frontal neurosurgical procedures, for BIS showed a strong correlation between frontal and occipital montage during propofol/fentanyl anaesthesia.

Figure 3: Electroencephalographic wave changes with deepening of anaesthesia, illustrating the Bispectral Index and Bispectral descriptors

Use of BIS
BIS monitoring has two main goals. First of all, it helps the anaesthesiologist to adjust the dosage of anaesthetic drugs and therefore speed the postanaesthesia recovery. Several studies have demonstrated that for an anaesthesiologist using propofol, nitrous oxide and alfentanil, adjusting the propofol infusion rate to obtain a BIS of 4560 during maintenance and 6075 during the last 15 min reduced the infusion rate of propofol compared with standard practice. It also decreased the time for return of responsiveness to commands

and eligibility for discharge from the recovery room.33 Similar findings were reported with desflurane or sevoflurane anaesthesia except that postanaesthesia care unit stay was not affected. With sevoflurane, the delay for return of responsiveness to commands was only marginally reduced, despite the statistical significance. A Finnish group confirmed that using BIS to guide administration of propofol or sevoflurane significantly reduces drug use and speeds return of consciousness (significant difference in the propofol group only).34 A Turkish study investigated in 2006 the role of using the BIS in recovery from anaesthesia

and altering drug administration in patients undergoing craniotomy for a supratentorial surgery. Fifty American Society of Anaesthesiologists' (ASA) physical status I-II patients undergoing craniotomy were included in the study. The patients were randomly divided into two groups, and all patients received standard induction drugs, and 0.8%-1.5% sevoflurane was used for maintenance of anaesthesia. In the BIS-guided group, the concentration of sevoflurane was titrated to maintain BIS at 40-60. In the control group, the anaesthesiologist was blind to BIS, and the concentration of sevoflurane was changed according to the patients' hemodynamic changes. The hemodynamic data, BIS values, and sevoflurane concentrations were recorded every 15 minutes. In addition, the BIS value was recorded by the primary anaesthetist in the BIS-guided group and by another independent anaesthetist in the control group. At the end of the study, recovery criteria and Aldrete recovery scores were recorded every 15 minutes. Neurologic assessments were performed when the Aldrete score was 9-10. BIS values were higher, and sevoflurane concentrations and total doses of fentanyl were lower, in the BISguided group. Times to first spontaneous breathing, eye opening, and extubation were significantly shorter in the BIS-guided group. Time to an Aldrete score of 9-10 and adequate neurologic assessment were similar between the groups. In conclusion, BIS monitoring by supratentorial craniotomy under general anaesthesia reduced the maintenance anaesthetic concentration and narcotic drug usage and lowered the recovery times from general anaesthesia.35 BIS monitoring also claims to prevent cases of awareness, but this is the most controversial point concerning BIS monitoring. Sebel et al. have prospectively documented the occurrence of awareness during general anaesthesia in a large group of patients treated in several hospitals in the United States. They found the incidence of awareness in their study (0.13%) to be comparable with that previously reported in other countries. Roughly 40% of their patients were monitored with the Bispectral Index (BIS) and, interestingly, the BIS-monitored group had a higher incidence of awareness (0.18%) than the control cohort (0.10%).36 A large Scandinavian study found BIS monitoring to be associated with a 77% reduction in the incidence of awareness when compared to historical controls. The BIS monitor was introduced into several institutions and the anaesthesiologists were instructed to use it in all cases were muscle relaxants were given and to maintain a BIS score below 60 during intubation and surgery. Around half of the patients in that study had a mean BIS score below 40 during maintenance of anaesthesia.37 Another recent study, the B-Aware

trial, was a randomized controlled trial confined to patients at high risk of awareness that found BIS monitoring led to an 82% reduction in the incidence of awareness. 38 One can also see the remarkable contradiction between the claims that BIS monitoring can reduce drug use and speed recovery while at the same time decreasing the incidence of awareness. Titrating doses of general anaesthetics according to BIS may increase the doses of muscle relaxants, and increased reliance on muscle relaxant combined with low level of anaesthetic concentrations certainly increases the chance of awareness. BIS also finds its use in intensive care, where it can be used to monitor patients with different critical illnesses. Monitoring critically ill, brain-injured patients with a decreased level of consciousness is challenging. An American study conducted in 2004 a prospective, single-blinded observational study to determine the correlation between the Bispectral Index (BIS) and three commonly used sedation agitation scales: the Richmond Agitation-Sedation Scale (RASS), the Sedation-Agitation Scale (SAS) and the Glasgow Coma Scale (GCS) scores. They found a statistically significant correlation between BIS values and the RASS, SAS, and GCS scores in critically ill brain-injured patients, with and without sedation, so the newer BIS XP software package may be a useful adjunctive tool in objective assessment of level of consciousness in braininjured patients.39 Different anaesthetic techniques have been suggested for craniotomy with intraoperative awakening. A Portuguese study33 describes an asleep-awake-asleep technique with propofol and remifentanil infusions, with pharmacokinetic simulation to predict the effect-site concentrations and to modulate the infusion rates of both drugs, and bispectral index (BIS) monitoring. Five critical moments were defined: first loss of consciousness (LOC1), first recovery of consciousness (ROC1), final of neurologic testing (NT), second loss of consciousness (LOC2), and second recovery of consciousness (ROC2). A significative correlation was found between BIS and predicted effect-site concentrations of propofol (r=0.547, P<0.001) and remifentanil (r=0.533, P<0.001). Multiple regression analysis between BIS and propofol and remifentanil predicted effect-site concentrations at the different critical steps of the procedure was done and found also significative (r=0.7341, P<0.001). Recent evidence suggests that BIS may also help in the detection of cerebral ischemia and prognostication of outcome of traumatic brain injury (TBI). An Indian study40 was designed to investigate the correlation between Glasgow Coma Score (GCS) and BIS in mild and moderate head

injury. In patients with mild and moderate head injury, significant correlation exists between GCS and BIS. But the high degree of scatter of BIS values for any given GCS score limits its use as a monitor of depth of coma in TBI. Further studies are required to understand the relation between BIS algorithm and cerebral electrical activity following TBI to define the role of BIS as an electrophysiological correlate of consciousness in TBI.

BIS values and which is even more important, in most cases the BIS signal quality indicator displays optimal signal quality.49 So, none of these subtle signal pollutions was detected by the BIS monitor and hence were not displayed as artefacts, thus opening the potential for inadvertent anaesthetic overdose. Effect of different clinical conditions on BIS monitoring During hypoglycaemia we can see on the EEG an increase in the and waves, combined with decrease in waves, a pattern very much similar to that of general anaesthesia.50 Hypothermia produces a linear decrease in inhaled anaesthetic requirements, but no study with sufficient sample size has been conducted yet to investigate the association between BIS and temperature.51 Abnormal EEG patterns After fully regaining consciousness after electroconvulsive therapy, patients in the post-ictal state display a peculiar EEG pattern in the form of very slow waves, a pattern very much resembling deep anaesthesia.52 As the BIS algorithm was developed from volunteers with normal EEG, neurological disorders that manifest abnormal EEG patterns such as Alzheimers type dementia or cerebral palsy mentally retarded children, will affect the BIS monitoring. Also, it is essential to confirm a normal BIS value in all patients before induction of anaesthesia, since 10% of the population has a genetically determined lowvoltage EEG variant, which is not associated with any brain dysfunction. 53-55 BIS electrodes are intended to detect cortical EEG signals. However, in the absence of EEG signals, as in brain dead subjects or extreme EEG suppression of deep hypothermia, the BIS algorithm is very vulnerable to a wide range of artefact signals, such as radiofrequency pollution or ECG signals. EMG activities are artefact signals that occur within the frequency range of interest of the bispectrum, because the EMG frequencies overlap the BIS algorithms BetaRatio. Therefore, contamination of BIS by EMG activity is inherent in the calculation of the BIS values. The administration of neuromuscular blocking drugs (NMBD) would decrease the BIS value by alleviating the artefact and unveiling the true calculated BIS.56 Cost-effectiveness A Finnish randomized study34 using eighty patients undergoing general narcosis, using propofol or sevoflurane demonstrated that BIS monitoring improved the immediate recovery after propofol anaesthesia, while no differences were

Limitations of BIS
Paradoxical BIS changes with anaesthetics Each type of anaesthetic has a different effect on the BIS monitor. Some anaesthetics are even found to be incompatible with BIS monitoring as such. After discontinuation of Nitrous Oxide (N2O) for example, we can see a paradoxical decline in BIS values, due to N2Os peculiar withdrawal-suppression EEG phenomenon., which is an overswing of paroxysmal bursts of lowfrequency and waves, a pattern very similar to that of deep anaesthesia. Also, N2O has a weak cortical action, because it acts mainly through activating the descending inhibitory noradrenergic pathway in the brainstem and spinal cord. This effect is completely undetectable by the algorithm that computes the BIS. That is why N2O, both as a sole anaesthetic and as an adjunct to IV anaesthesia results in loss of consciousness without a noticeable change in BIS values.41,42 Ketamine as well, doesnt follow the basic EEG pattern of general anaesthesia, so logically neither do the BIS values.43 We also see that different anaesthetics have different EEG signatures, so BIS values are not the same for equipotent concentrations of different inhaled anaesthetics.44 For example, the BIS algorithm, which was not written or validated for halothane, does not accurately reflect the hypnotic effect of halothane anaesthesia and my lead to inadvertent halothane overdose.45,46 Since noncortical structures, such as the locus coeruleus-noradrenergic system that are undetectable by the EEG, are involved in the mechanism of opioids drug effect, opioids in analgesic concentrations produce minimal or no electrophysiological alterations on the cerebral cortex. However, opioids may still influence BIS monitoring by their agonist activity, enhancing the hypnotic effect of propofol. BIS doesnt show this increased effect and could hence lead to a possible anaesthetic overdose.47,48 Electrical interference Electrical devices, such as electrocautery, pacemakers, forced-air warming blankets or endoscopic shoulder shavers can all give abnormal

seen in patients receiving sevoflurane. The consumption of both propofol and sevoflurane decreased significantly (29% and 40%, respectively). However, BIS monitoring increased direct costs in these patients; the break-even times (704 min for propofol and 282 min for sevoflurane) were not reached. Detailed cost analysis showed that the monitoring increased direct costs of anaesthesia treatment in these patients, mainly due to the price of special EEG electrodes used for relatively short anaesthesias. Paventi and colleagues 57 investigated in another study total drug costs in either the BIS or CS group and the cost of BIS monitoring. They found that total drug cost was lower in the BIS group when compared to that in the CS group (0.699 versus 0.984 euro/70kg patient), but they didnt bring the cost of the BIS device into account. As the BIS algorithm is constantly being refined and updated to filter out these artefacts and to synchronize it with new types of anaesthetics, different studies have already demonstrated that newer models provide different values for the same hypnotic levels, making it absolutely necessary for anaesthesiologists in the daily practice to realize which type of monitor they use, in order to read the BIS values correctly. So, in addition to all the above-mentioned factors, the choice of the BIS model is a major factor that would greatly influence the interpretation of the BIS value.

Conclusion It should be noted that the bispectral index is a work in progress. As new anaesthetic agents are developed and used, the BIS algorithm is continually retested and refined. In addition, the

algorithm is proprietary information, which means that it is kept secret by the company that developed it. Other anaesthesia monitoring systems that are in use as of 2003 include the Patient State Analyzer, or PSA 4000, which is also based on EEG data; and the A-Line (R) monitor, which processes signals derived from auditory stimuli. Also, Spectral Entropy (SpEn) is an alternative tool to the BIS for monitoring depth of hypnosis. Current opinion among anaesthesiologists appears to be that none of the present monitoring systems are sufficiently sensitive to guarantee that patients will not awaken during surgery while simultaneously preventing undesirable cardiovascular reactions, other stress responses, or overuse of anaesthetic agents. 58 The view that the search for a reliable index of anaesthetic depth should be transformed into a search for separate indices of different components of anaesthesia has been addressed in a number of articles. The common conclusion was that a monitor of anaesthesia may measure only one of the components of general anaesthesia, such as loss of consciousness, obtunding motor response, or hemodynamic response to noxious stimulation. Is the BIS a measure of the depth of anaesthesia? As we indicated above, different components of anaesthesia have different underlying mechanisms; therefore, it is difficult to expect that a single index can be used successfully for measuring the depth of anaesthesia in general. The opinion of investigators familiar with the BIS is very certain. Glass et al. state that individual anaesthetics each produce a unique spectrum of pharmacologic actions, so the concept of a common depth of anaesthesia may need to be revisited to reflect the separate clinical components of the ideal anaesthetic state. Consequently, a monitor of depth of anaesthesia may measure only one of these components.59

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