*Presented in part at the 7th International Symposium on Memory and Awareness in Anaesthesia, Munich, March 2008.
The ability of bispectral index to detect intra-operative wakefulness during isoflurane/air anaesthesia, compared with the isolated forearm technique†
Article first published online: 12 SEP 2013
© 2013 The Association of Anaesthetists of Great Britain and Ireland
Volume 68, Issue 10, pages 1010–1020, October 2013
How to Cite
Russell, I. F. (2013), The ability of bispectral index to detect intra-operative wakefulness during isoflurane/air anaesthesia, compared with the isolated forearm technique. Anaesthesia, 68: 1010–1020. doi: 10.1111/anae.12357
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- Issue published online: 12 SEP 2013
- Article first published online: 12 SEP 2013
- Manuscript Accepted: 6 JUN 2013
Clinical signs are unreliable for guiding anaesthetic administration and it is suggested that using the bispectral index can improve anaesthetic delivery. In the current study, isoflurane administration was guided to a bispectral index range of 55–60. Intra-operative responsiveness, as assessed by the isolated forearm technique, was compared with whether the bispectral index predicted/identified a patient's appropriate hand movements in response to commands. Thirty-four women underwent major gynaecological surgery with isoflurane/air and atracurium. Eleven women responded on 32 occasions with appropriate hand movements to commands given during surgery, of which the bispectral index detected 17 (sensitivity 53%). The bispectral index suggested consciousness 660 times in the absence of any movement responses (specificity 69%). The positive predictive value of the bispectral index was 3%. The median (IQR [range]) bispectral index value associated with an intra-operative response was significantly lower than that associated with eye opening after surgery: 60 (50–68 [36–83]) vs 77 (75–84 [59–90]), respectively (p = 2.25 × 10−8). Conversely, end-tidal isoflurane concentration was significantly higher at intra-operative response than at eye opening: 0.3 (0.3–0.4 [0.2–0.9]) vs 0.2 (0.1–0.2 [0.1–0.3]), respectively (p = 7.36 × 10−8). For patients who responded more than once during surgery, the bispectral index value associated with a response was not constant. No patient had recall for surgery or the taped commands, and only one could remember dreaming (a good dream). Titrating isoflurane to target a bispectral index range of 55–60 may result in an unacceptable number of patients who are conscious during surgery (albeit without recall).
In terms of reducing the incidence of awareness with recall (AWR), there is continued debate as to the benefits of using anaesthesia brain monitors (ABM) during inhalational anaesthesia. Some studies support such a claim [1, 2], while others show no benefit [3-5]. Despite this debate, use of ABM has been recently endorsed in national guidelines , and other influential sources suggest that ABM-guided anaesthesia should be used to ‘improve anaesthetic delivery, decrease consumption of anaesthetic drugs with associated costs savings, and enhance postoperative recovery, while at the same time reducing the incidence of AWR' .
Apart from the additional costs, adding an ABM to the range of monitors already in use is unlikely to do harm, but the situation is less clear when using an ABM deliberately to reduce the administration of general anaesthesia drugs. For example, Sneyd argues that while using BIS to confirm that a patient is deeply anaesthetised may be reassuring, using it to ‘skate on thin ice’ may be ‘dangerous territory’ . Indeed, using an ABM to reduce anaesthetic delivery might actually increase the incidence of AWR [5, 9]. Although there were no reports of AWR in the studies reviewed in a meta-analysis , the total number of cases was small (928). In these studies , despite no AWR reported, we know nothing of the intra-operative conscious state of the patients. For AWR, two things are required: the patient must have been conscious during the procedure; and in the postoperative period, the patient must be able to recall that same episode of the intra-operative consciousness. Studies with the isolated forearm technique (IFT) have shown that many patients can be conscious (sometimes in pain) and able to respond to simple or complex intra-operative commands, yet have no recall for this in the postoperative period [10-13]. This intra-operative responsive state with no subsequent recall was first described by Tunstall as ‘wakefulness’ . Neuromuscular blocking drugs prevent patient movement, making it perhaps more difficult or impossible to ascertain whether the patient is conscious, and it is noteworthy that in those studies analysed by Punjasawadwong et al. , the vast majority of patients (818/928) received non-depolarising neuromuscular blocking drugs.
Whether or not ABM-guided anaesthesia reduces anaesthetic delivery (without AWR), no evidence has ever been produced that patients undergoing such general anaesthesia remain unconscious during their surgical procedure. If patients were, in fact, wakeful but paralysed, then the long-term consequences may not be benign since some patients with no explicit memory of surgery may nonetheless develop psychiatric problems as a result of implicit memory [15, 16]. However, quite apart from the long-term consequences for patients, there are serious moral and ethical issues involved when operating on conscious patients, who may or may not be in pain, and who expect to be unconscious, even if the patients have no subsequent recall [17-19].
Of the available ABMs, the most widely studied is the bispectral (BIS) monitor and the current study sought to use manual adjustment of the inhaled isoflurane concentration to keep the BIS index in the recommended range 55–60 and to observe the incidence of intra-operative responsiveness to command as assessed by the IFT. The prediction was that, if BIS in this range reliably prevents wakefulness, then there would be no IFT responses. Thereby, it was planned to (a) evaluate the utility of the BIS index to predict/identify patient responses to commands; (b) compare the BIS index during any intra-operative responsiveness with that at eye opening to command at the end of surgery; (c) compare the end-tidal isoflurane concentration at any intra-operative response with that at eye opening to command at the end of surgery.
Following ethical approval from the Local Research Ethics Committee, women undergoing major gynaecological surgery gave written informed consent to this study. The BIS monitor (BIS A 2000, Revision 3.01: Covidien Medical, Boulder, CO, USA) guided the administration of isoflurane, in association with clinical signs and the IFT. Women aged > 60 or < 18 years of age, those with hearing difficulties, or of ASA physical status > 2 were not recruited. This was a convenience sample of patients, but given that the overall incidence of positive IFT responses is expected to be ~37% , a sample size of 30–35 patients would be expected to yield ~10–12 patients who responded at least once. This was regarded as a sufficient number to perform further data analysis.
The pre-operative interview, physiological monitoring, BIS monitoring, IFT methodology, and postoperative follow up were similar to a previous study using target controlled infusions (TCI) of propofol and remifentanil , and a detailed discussion of the IFT is presented elsewhere [21, 22].
In the anaesthetic room, a 16-G intravenous cannula was placed in the non-dominant forearm. For those patients in whom low thoracic epidural was planned, this was sited before induction of anaesthesia at ~T10 and 3 ml levobupivacaine 0.5% administered as a test dose, followed by a further 7 ml. The epidural was topped up with further 10-ml increments of levobupivacaine 0.5% at 90–120 min intervals throughout surgery.
In the operating theatre, after baseline monitoring data had been obtained, a bolus of fentanyl (100 μg) was administered followed by an effect-site TCI of propofol , with initial effect site target concentration set at 6 μg.ml−1. The propofol was infused with an Alaris PK TCI infusion pump (Cardinal Health, 1180, Rolle, Switzerland). If consciousness was not lost at this target concentration (i.e. there was a response to the command, “Name, open your eyes”), then the target concentration was increased. When consciousness was lost, the IFT isolating cuff was inflated and atracurium (0.4 mg.kg−1) was given. During surgery, further bolus doses of atracurium (0.2–0.3 mg.kg−1) were given as required to facilitate surgical access, with appropriate inflation and deflation of the isolating cuff. Following intubation, the propofol TCI pump was switched off, and isoflurane was administered in an air/oxygen mixture, initially to target an end-tidal concentration of 1 MAC as indicated on the monitor (Datex Ohmeda, AS3; GE Healthcare, Buckinghamshire, UK). Thereafter, the isoflurane was manually adjusted to maintain the BIS in the range of 55–60. This range was chosen for two reasons: (a) the manufacturer's guidance states that a range of 45–60 is appropriate for balanced anaesthesia with opioids and that within this range, the patient will be ‘unresponsive to verbal stimuli’ [6, 24]; (b) to minimise anaesthetic agent use . If the BIS did rise > 60 with no IFT response and clinical signs remained stable, then anaesthesia was not deepened. Regardless of the BIS value, if a patient responded appropriately to command, then the isoflurane was increased. Because low flow (< 1 l.min−1) was used, the isoflurane vaporiser was turned to maximum until responding ceased (usually within a min). Additional propofol was administered via the TCI pump if responding did not stop despite this. If, on the other hand, response to command stopped spontaneously, then no change in the conduct of anaesthesia was instituted.
At the end of surgery, wake-up time was measured from when the isoflurane was turned off until the patients opened their eyes to command. Following eye opening to command, the tracheal tube was removed and the patient transferred to the recovery room. Before patients returned to the ward, they were interviewed by the author using a structured format  to investigate both implicit and explicit memory. Because of split hospital sites, it was not possible to perform follow-up interviews on subsequent days.
For data analysis, the definition of consciousness (i.e. wakefulness) was a verified response to command during IFT. The definition of a BIS index predicting/identifying consciousness in association with a patient response to command was as follows: a BIS index > 60 continuously for at least 60 s within the time period extending from 2 min before to 2 min after the patient's response. If the BIS index rose > 60 continuously in association with a hand movement response, and the BIS index was still > 60 at the time of a subsequent movement response, then it was assumed that BIS had also identified consciousness associated with this subsequent response. In the absence of any patient response to command, a BIS index > 60 continuously for at least 60 s was taken to indicate the mistaken prediction/identification of consciousness. A single BIS value < 60 in the 1-min time intervals was ignored.
Parametric and non-parametric statistical tests were used as appropriate with the statistical programme SPSS (v 19) (IBM Corporation, Armonk, NY, USA).
A total of 34 women were recruited (Table 1). Overall, some 2146 commands were played to the 34 patients. Excluding the eye opening response at the end of surgery, 11 (32%) women responded to commands during surgery. In total, these 11 women responded to command 32 times and of these, the BIS monitor detected 17 (Table 2). Patients responded to command over a wide range of BIS values (Table 2; Fig. 1). At the time of a response, the BIS trend may be upwards, downwards or stable and patients responding more than once often responded at different BIS values. With the wide disparity of BIS values at a response, the positive predictive value (PPV) of a BIS response was only 3% (Table 2; Fig. 1). Fifty-six per cent of the responses occurred in association with a BIS ≤ 60 and 34% in association with a BIS < 55 (Fig. 1).
|All patients (n = 34)||Responders (n = 11)||Non-responders (n = 23)|
|Age; years||47.2 (9.8)||48.1 (10.6)||46.7 (9.6)|
|Height; cm||163.1 (7.7)||167.7 (7.1)||161.1 (7.2)|
|Weight; kg||75.9 (17.4)||81.8 (15.5)||73.0 (17.8)|
|BMI; kg.m−2||29.4 (7.6)||29.8 (6.6)||29.2 (8.1)|
|Duration of anaesthesia; min||67 (51–96 [32–214])||77 (51–97 [32–214)||67 (53–85 [40–171])|
|Duration of tape; min||54 (39–73 [21–179])||63 (38–78 [21–179])||54 (40–69 [26–145])|
|Wake-up time||4.2 (1.9)||4.1 (1.5)||4.3 (2.0)|
|IFT response||No IFT response|
|BIS response||17||666||PPV = 3%|
|No BIS response||15||1448||NPV = 99%|
|Sensitivity = 53%||Specificity = 69%|
For the whole group (Table 3), the BIS values were significantly lower at intra-operative response to command than they were at eye opening after surgery. Conversely, the end-tidal isoflurane concentration in association with intra-operative response to command was significantly higher than that associated with eye opening after surgery (Table 3). When the data for only those patients who responded to command intra-operatively were examined, similar significant differences between the BIS values and isoflurane concentrations associated with intra-operative response to command and eye opening after surgery were revealed (Table 4).
|Intra-operative response||Eye opening||Significance|
|Instantaneous BIS||60 (50–68 [36–83])||77 (75–84 [59–90])||p = 2.25 × 10−8|
|BIS 30 s average||60 (50–67 [37–81])||79 (76–84 [67–92])||p = 4.73 × 10−10|
|End-tidal isoflurane %||0.3 (0.3–0.4 [0.2–0.9])||0.2 (0.1–0.2 [0.1–0.3])||p = 7.36 × 10−8|
|Intra-operative response||Eye opening||Significance|
|Instantaneous BIS||60 (50–68 [36–83])||77 (75–85 [70–90])||p = 1.79 × 10−6|
|BIS 30 s average||60 (50–67 [37–81])||80 (77–86 [69–92])||p = 6.84 × 10−7|
|End-tidal isoflurane %||0.3 (0.3–0.5 [0.2–0.9])||0.2 (0.1–0.2 [0.1–0.3])||p = 3.30 × 10−6|
At eye opening after surgery, there was no significant difference between the BIS values and isoflurane concentrations between those patients who responded during surgery and those who did not (Table 5).
|Responding group||Non-responding group||Significance|
|Instantaneous BIS||77 (75–85 [70–90])||77 (74–82 [59–88])||p = 0.70|
|BIS 30 s average||80 (77–86 [69–92])||78 (67–83 [67–92])||p = 0.94|
|End-tidal isoflurane %||0.2 (0.1–0.2 [0.1–0.3])||0.2 (0.1–0.2 [0.1–0.3])||p = 0.62|
Figures 2 and 3, sections of the BIS/electromyography (EMG) record from two different patients, illustrate the difficulties of using BIS to guide isoflurane administration in the presence of significant EMG activity. In both these cases, a high BIS appears related to significant EMG activity. In Fig. 2, initially, the BIS was 60 and there were no responses to command. At 78 min, there was a rapid rise in BIS and EMG, but as there was no response to command, a bolus of atracurium was given (in response to the increased EMG activity). Following this, both EMG and BIS returned rapidly to the previous baseline. At ~93 min, BIS and EMG again increased. At this time, there was a reflex movement of the hand (i.e. not associated with the command) and because the BIS remained high, the isoflurane was increased. This had little effect on the BIS or EMG, and a bolus of atracurium was given. After the atracurium, despite reducing the isoflurane at this point, both EMG and BIS declined to their baseline levels. The BIS at eye opening was 75.
As shown in Fig. 3, the BIS was initially low, when there was a reflex hand movement accompanied by a rise in the EMG and BIS. As there was no response to command, a bolus of atracurium was given. Both the EMG and BIS rapidly declined to < 50, but while the BIS was declining, the patient responded to command. At this point, the isoflurane was increased and within 1 min, the patient stopped responding to command. Later, at ~48 min, with the BIS again declining to between 50 and 40, the patient responded to command and both the EMG and BIS increased. After the isoflurane was increased, the patient responses stopped within 1 min and both the BIS and EMG declined rapidly. The BIS at eye opening was 72.
The BIS was > 60 for 60 s or more for 25 (15–58 [0–87])% of the time between tape-on and tape-off, with no statistically significant difference between those who responded to command and those who did not: 17 (2–44 [0–51])% vs 32 (15–58) [0–87])%, respectively (p = 0.113). For all patients, the proportion of instantaneous BIS values > 60 was 35 (16–52 [2–94])% and (perhaps paradoxically) patients who did not respond spent a significantly greater proportion of the time with a BIS index > 60: 40 (24–64 [3–94])% vs 22 (9–40 [2–60])%, respectively, p = 0.05.
The relationship between BIS and end-tidal isoflurane concentration is shown for some patients in Fig. 4. The coefficient of determination for these data indicates that changes in isoflurane concentration account for only some 1–6% of the variation in BIS output.
There was no difference in the wake-up times between patients who responded to command and those who did not respond. For the whole group, the wake-up time was 4.0 (2.7–5.6 [1.3–9.1]) min and for responders and non-responders, it was 4.5 (2.8–5.0 [2.3–6.8]) min and 3.8 (2.6–5.7 [1.3–9.1]) min, respectively (p = 0.89).
On direct questioning, four patients (two responders, two non-responders) remembered extubation, but apart from this, there was no other evidence of explicit recall for surgery or for the tape. There was no evidence of implicit memory for the information provided on the tape during surgery. Only one patient, who did not respond to commands, remembered dreaming: it was a good dream, but she could not remember the content.
At no time was the neuromuscular integrity of the isolated hand affected. Train of four was always 4 and a tetanic stimulus was well maintained.
This is probably the first investigation that directly investigates intra-operative responsiveness with the IFT, for the duration of major surgery, during BIS-guided isoflurane anaesthesia in the presence of neuromuscular blocking drugs. The levels of BIS to which isoflurane was titrated conform to recommended practice [7, 24] and advice from regulatory bodies . However, with 11/34 women responding to commands (i.e. conscious) during surgery, the results do not support the notion that keeping the BIS in the range 55–60 is necessarily an appropriate anaesthetic technique.
Indeed, it was difficult in practice to maintain BIS in such a narrow range when manually adjusting isoflurane, and 35% of the time the ‘instantaneous’ BIS value was > 60 (30% of this time the BIS value was between 60 and 65). A further consideration is the accuracy of the BIS in identifying ‘consciousness’ under these conditions. Using a definition of consciousness as a BIS value > 60 for 60 s, the sensitivity of the BIS was only 53%. If the more clinically convenient ‘real time’ BIS index (as shown on the monitor) is used, then the sensitivity is only 44%. It is suggested that BIS can be allowed to increase to ~70–80 towards the end of surgery [7, 25, 26], implying that at these values, the patient will still be unconscious. Yet, in the current study, 22 (65%) patients opened their eyes to command at BIS values of 60–80 after surgery, suggesting that these values (if they are meaningful at all) are too high to guarantee unconsciousness at this time point, especially as BIS at intra-operative response to command is lower than at eye opening.
Few studies have employed the IFT. Indeed, it appears that the IFT is used as a monitoring technique by just 14 of > 8000 practitioners in the UK . In my previous study of Narcotrend-guided target-controlled infusion (TCI) propofol anaesthesia , all 12 patients responded to command during surgery. In a more recent study of BIS-guided TCI propofol anaesthesia, 73% of patients responded to command during surgery . In two studies investigating patients before surgery started [28, 29], the Narcotrend, the BIS index and Patient State Index were unable reliably to detect (un)consciousness. The data from the current study, together with these four studies [13, 20, 28, 29], suggest that, in the presence of neuromuscular blocking drugs, ABMs are not able to identify the return of consciousness with any reliability. Pandit and Cook, reviewing large-scale trial data on ABMs, also concluded that they exhibited poor performance as diagnostic tools with a sensitivity and specificity of ~50%, and a positive predictive value of 0.2%, broadly similar to the data in Table 2.
The relationship between (1) BIS values at intra-operative response and at eye opening after surgery, and (2) isoflurane concentration at intra-operative response and at eye opening after surgery, seems contradictory. The BIS was significantly lower in association with response to commands during surgery than at eye opening, and the end-tidal isoflurane concentration associated with an intra-operative response was higher than the concentration at eye opening. That a greater concentration of isoflurane was required to prevent responsiveness in the presence of surgical stimulation is not surprising (the dose of epidural local anaesthetic used was not intended for an extensive surgical block but rather to ensure good analgesia in the postoperative period). However, the lower BIS values in association with intra-operative responses are more difficult to explain, and have been noted before . One explanation (although not one that favours the BIS as a monitoring tool) is that the relationships between BIS and both isoflurane concentration and patient consciousness are simply very variable, such that a given isoflurane concentration or level of consciousness does not result in a unique BIS value [30-33]. In line with this, the data from this study indicate that only around 1–6% of the variation in BIS is related to the end-tidal isoflurane concentration (Fig. 4).
It is possible that patients who respond during IFT belong to a different subpopulation of patients from those who do not respond. ‘Responders’ may be relatively insensitive to isoflurane and/or exhibit response to command at lower BIS values, for example, due to a genetically determined low-voltage EEG , or other genetic factors . However, such reasons seem unlikely. A genetically related low-voltage EEG is present in only 5–10% of the population  and the proportion of responding patients in this study was 35% (and in a previous study 73% ). Moreover, there was no difference in the BIS or the ET isoflurane concentration at eye opening after surgery between the responders and non-responders, nor was there any difference in the wake-up times.
As discussed previously , a major problem in this type of study relates to the definition of a BIS response indicative of consciousness. There is no agreement as to what might constitute a ‘BIS response’ to a particular event. Re-analysing the results of this current study using an instantaneous BIS value at the time of the response, or the BIS value averaged over 30 s after the response, made no difference to the overall results.
As in the previous study , sudden rises in the BIS were often associated with an increase in EMG activity, but with no response to command. A bolus of atracurium in these circumstances resulted in the EMG and BIS declining back to their baseline. It is known that the EEG and EMG frequencies overlap in the 35–47 Hz range and this EMG activity is interpreted by the BIS monitor as high-frequency, low-amplitude waves, falsely elevating the BIS [36, 37]. Figures 2 and 3 demonstrate how such ‘contamination’ from the EMG signal can result in high BIS values and when the EMG signal disappears, either spontaneously or after atracurium, the high BIS index values return to their previous values. An EMG contribution to the BIS could also be an explanation why the BIS was apparently higher at eye opening after surgery than during intra-operative responses to command: during surgery, neuromuscular blockers may limit the EMG contamination of the BIS signal resulting in an artificially low value, but at the end of surgery, when the blockade is reversed, there will be increased EMG activity and an associated higher BIS. It is possible that these EMG-driven BIS responses during surgery could be prevented by maintaining near complete muscle paralysis, but whether this would result in a more reliable BIS indication of intra-operative consciousness is not known.
Several studies have concluded that BIS monitoring is no better than end-tidal agent monitoring in preventing AWR [3-5]. The results of the current study would lend support to such a view. In those studies [3-5], the lower end-tidal concentration limits for inhalational anaesthetics were set at either 0.5 or 0.7 of age-corrected MAC. In the current study, only one patient responded with an end-tidal isoflurane concentration > 0.5 MAC. She had been extremely anxious pre-operatively and during the initial opening of the abdomen, from pubis to xiphisternum, she responded twice over a 2.5-min period. At the first response, end-tidal isoflurane was 0.4% (BIS = 51, MAC = 0.33) and at the second response, end-tidal isoflurane was 0.9% (BIS = 61, MAC = 0.75) at which point, TCI propofol was recommenced for a short time. She had an epidural in situ, and on both occasions, she indicated that she was comfortable. During this 2.5-min period, the BIS index had gradually increased to 63 (at 1.25 min) and then began to decline. Although the BIS response was > 60 for just over 60 s, it is unlikely that this would have triggered any alteration in anaesthetic management in normal practice (i.e. without IFT response information). It has already been pointed out  that the lack of knowledge as to what might constitute a BIS response to intra-operative consciousness creates some doubt as to the validity of the NICE recommendations .
The current study has its limitations. Defining consciousness is difficult. However, with regard to general anaesthesia, it is accepted that when patients are not paralysed, then a patient's sensible intra-operative motor response to a command (e.g. “Name name, open your eyes”, or “name, name squeeze my fingers”) would indicate that the patient is conscious and therefore anaesthesia is inadequate [19, 39]. The IFT is simply a means to allow a paralysed patient to respond to command  and thus if a patient responds to command in the presence of neuromuscular blocking drugs, then that patient should logically be regarded as conscious. Some will argue that the BIS target range of 55–60 is too near the ‘margins of consciousness’ . However, current BIS guidance indicates that 45–60 is acceptable [6, 7, 24] and there are recommendations that one should allow the BIS index to rise to between 60 and 80 near the end of surgery [7, 25, 26]. This criticism  seems unjustified. Tighter control of BIS to keep it < 60 (perhaps using an automated feedback system) may have better prevented responsiveness. This seems unlikely, as 56% of IFT responses occurred at a BIS < 60, and 34% at a BIS < 55. The concentrations of isoflurane used were much lower than a recommendation that agent levels should be > 0.5–0.7 MAC [3-5]. However, these recommendations are really aimed at managing paralysed patients during ‘blind’ administration of agents, rather than when the IFT is used as a measure of responsiveness.
One patient in the current study remembered dreaming. While it has been suggested that dreaming implies a form of (unconnected) consciousness , the interpretation of any particular dream (especially as in this case, its content could not be remembered) is difficult.
While it is possible that additional interviews later in the postoperative period may have uncovered further evidence of recall , this seems unlikely. In previous IFT studies, additional interviews did not reveal additional recall [11, 42]; the IFT probably identifies an early level of consciousness where no encoding of events into long-term memory occurs.
In conclusion, the finding that BIS correlates very poorly with intra-operative responsiveness as measured by IFT has important implications for guidelines promoting the use of BIS to prevent awareness with recall, or to reduce the administration of anaesthetic agent.
I am indebted to Professor Michael Wang (Professor of Clinical Psychology, University of Leicester) for his comments on the manuscript. The BIS monitor and electrodes were purchased from funds raised by the 6th International Symposium on Memory and Awareness, Hull, 2004.
No funding or competing interests declared.
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