This Invited Commentary accompanies the following original article:
Shanks AM, Avidan MS, Kheterpal S, et al. Alerting thresholds for the prevention of intraoperative awareness with explicit recall. A secondary analysis of the Michigan Awareness Control Study. Eur J Anaesthesiol 2015; 32:346–353.
In the present issue of the European Journal of Anaesthesiology, Shanks et al.1 present a secondary data analysis of the Michigan Awareness Control Study (MACS).2 As previously demonstrated by the research group, the incidence of awareness during anaesthesia may be reduced if an alarm is provided when either Electroencephalography (EEG) bispectral index (BIS) rises above, or end-tidal anaesthetic concentration (minimum alveolar concentration, MAC equivalents) falls below, a predefined threshold.3,4 So far, these thresholds had been given by study protocols. Therefore, the authors tried to use data from the MACS study to determine the optimum alerting threshold.
Alerting was performed on the basis of the perioperative information system with an automated real-time analysis of BIS and MAC values. Unfortunately, the system performed real-time analysis only every 5 min and an alarm was given only if the median value of the last 5 min was higher (BIS) or lower (MAC) than the given threshold.3 This may be one of the major limitations of the study, because this approach ignores shorter periods with BIS or MAC outside the target ranges.
Currently, we have only limited knowledge about reasons for memory formation during anaesthesia awareness. It has been shown that the probability of awareness with recall increases with lighter levels or longer duration of insufficient levels of anaesthesia, but memory may also be established during shorter periods of insufficient anaesthesia.5 Therefore, the 5-min average of BIS and MAC may have missed significant increases of BIS or decreases of MAC concentrations.
Despite this limitation, the data analysis revealed an interesting finding. For both MAC and BIS, an optimum threshold for prevention of awareness should be determined. On the one hand, a high threshold value for MAC/low value for BIS may lead to overalarming with subsequent desensitisation to the alarms but, on the other hand, a low threshold value for MAC/high value for BIS may miss awareness cases.
In their first study in a patient group with increased risk of awareness, the research group used 0.7 MAC equivalents as the alerting threshold.6 The same threshold was used in the BAG-RECALL study.7,8 In the next step, the MACS study was performed to evaluate efficacy of BIS versus MAC alerts in the general population. For the MACS study, the alerting threshold for the volatile anaesthetic was decreased to 0.5 MAC equivalents. The authors lowered the threshold according to analysis of their own data, wherein a MAC threshold of 0.5 had a high positive likelihood ratio.9 The threshold was also lowered because the 0.7 MAC threshold was frequently crossed in one of the previous studies.6
With a threshold of 0.5 MAC, the number of reported alarms in the MAC-triggered group was lower than in the BIS-triggered group, whereas a threshold towards 0.7 MAC would have increased the number of alarms. This suggests that a threshold of 0.5 MAC may be too low, at least when compared with a BIS threshold of 60.
This is consistent with observations of the MACS study. In this study, the alarming did not work in all operating rooms. Therefore, patients in whom alarming failed were pooled posthoc into a ‘no intervention group’. Compared with this group, both BIS and MAC alarming showed a trend towards lower incidences, but only if possible and definite awareness were pooled. In the BIS group, this trend seemed more pronounced than in the 0.5 MAC group. It must be assumed that the difference between alarming on the basis of BIS or MAC is – at least in part – due to the lowering of alerting from 0.7 to 0.5 MAC equivalents.
Both approaches, MAC and EEG-based alerting, may reduce the incidence of possible and definite awareness, even if the optimum alerting threshold remains undetermined.
The current approaches use either BIS or MAC equivalents to trigger an alarm. Recent data suggest that a combination of both standard parameters (including end-expiratory anaesthetic concentration) and EEG parameters reflects the level of anaesthesia better than each of these parameters alone.10 With the use of surrogate parameters as a measure of consciousness, a combination of multiple monitoring modalities (i.e. inclusion of both BIS and MAC equivalents) may lead to a further reduction of awareness.
In the last decade, animal and human studies have increased our knowledge about mechanisms behind anaesthesia-induced unconsciousness. Functional magnetic resonance imaging (fMRI) provides information about functional connectivity between different areas of the brain. It has been shown that anaesthesia-induced unconsciousness is related to a decrease of cortico-cortical and thalamo-cortical connectivity in fronto-parietal networks.11 This change has been observed in both functional (fMRI) and effective connectivity.12 Cross-approximate entropy (xApEn) of the EEG has been used to assess directed information transfer between cortical areas. With loss of consciousness, fronto-parietal feedback is decreased, although feed-forward information transfer is maintained. This may reflect the mechanism of anaesthesia-induced unconsciousness, and is observed with a variety of anaesthetics, including propofol, sevoflurane and ketamine.13,14 As a consequence, targeting these changes in EEG pattern for detailed analysis may provide a more direct measure of consciousness. The future application of such a specific parameter would allow more definite detection of awareness and facilitate a move from a probabilistic surrogate to mechanism-based-monitoring of anaesthesia induced unconsciousness, and finally the prevention of intraoperative consciousness.
Acknowledgements relating to this article
Assistance with the commentary: none.
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Conflicts of interest: none.
Comment from the editor: This invited commentary was checked and accepted by the editors but was not sent for external peer review.
1. Shanks AM, Avidan MS, Kheterpal S, et al. Alerting thresholds for the prevention of intraoperative awareness with explicit recall. A secondary analysis of the Michigan Awareness Control study. Eur J Anaesthesiol
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