Mehrnaz Shoushtarian1, Marko M Sahinovic, Anthony R Absalom, Alain F Kalmar, Hugo E M Vereecke, David T J Liley, Michel M R F Struys. 1. From the *Cortical Dynamics Ltd., North Perth, Western Australia, Australia; †Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; ‡Brain and Psychological Sciences Research Centre, Swinburne University of Technology, Hawthorn, Victoria, Australia; and §Department of Anesthesia, University of Ghent, Ghent, Belgium.
Abstract
BACKGROUND: Current electroencephalogram (EEG)-derived measures provide information on cortical activity and hypnosis but are less accurate regarding subcortical activity, which is expected to vary with the degree of antinociception. Recently, the neurophysiologically based EEG measures of cortical input (CI) and cortical state (CS) have been shown to be prospective indicators of analgesia/antinociception and hypnosis, respectively. In this study, we compared CI and an alternate measure of CS, the composite cortical state (CCS), with the Bispectral Index (BIS) and another recently developed measure of antinociception, the composite variability index (CVI). CVI is an EEG-derived measure based on a weighted combination of BIS and estimated electromyographic activity. By assessing the relationship between these indices for equivalent levels of hypnosis (as quantified using the BIS) and the nociceptive-antinociceptive balance (as determined by the predicted effect-site concentration of remifentanil), we sought to evaluate whether combining hypnotic and analgesic measures could better predict movement in response to a noxious stimulus than when used alone. METHODS: Time series of BIS and CVI indices and the raw EEG from a previously published study were reanalyzed. In our current study, the data from 80 patients, each randomly allocated to a target hypnotic level (BIS 50 or BIS 70) and a target remifentanil level (Remi-0, -2, -4 or -6 ng/mL), were included in the analysis. CCS, CI, BIS, and CVI were calculated or quantified at baseline and at a number of intervals after the application of the Observer's Assessment of Alertness/Sedation scale and a subsequent tetanic stimulus. The dependency of the putative measures of antinociception CI and CVI on effect-site concentration of remifentanil was then quantified, together with their relationship to the hypnotic measures CCS and BIS. Finally, statistical clustering methods were used to evaluate the extent to which simple combinations of antinociceptive and hypnotic measures could better detect and predict response to stimulation. RESULTS: Before stimulation, both CI and CVI differentiated patients who received remifentanil from those who were randomly allocated to the Remi-0 group (CI: Cohen's d = 0.65, 95% confidence interval, 0.48-0.83; CVI: Cohen's d = 0.72, 95% confidence interval, 0.56-0.88). Strong correlations between BIS and CCS were found (at different periods: 0.55 < R2 < 0.68, P < 0.001). Application of the Observer's Assessment of Alertness/Sedation stimulus was associated with changes in CI and CCS, whereas, subsequent to the application of both stimuli, changes in all measures were seen. Pairwise combinations of CI and CCS showed higher sensitivity in detecting response to stimulation than CVI and BIS combined (sensitivity [99% confidence interval], 75.8% [52.7%-98.8%] vs 42% [15.4%-68.5%], P = 0.006), with specificity for CI and CCS approaching significance (52% [34.7%-69.3%] vs 24% [9.1%-38.9%], P = 0.0159). CONCLUSIONS: Combining electroencephalographically derived hypnotic and analgesic quantifiers may enable better prediction of patients who are likely to respond to tetanic stimulation.
RCT Entities:
BACKGROUND: Current electroencephalogram (EEG)-derived measures provide information on cortical activity and hypnosis but are less accurate regarding subcortical activity, which is expected to vary with the degree of antinociception. Recently, the neurophysiologically based EEG measures of cortical input (CI) and cortical state (CS) have been shown to be prospective indicators of analgesia/antinociception and hypnosis, respectively. In this study, we compared CI and an alternate measure of CS, the composite cortical state (CCS), with the Bispectral Index (BIS) and another recently developed measure of antinociception, the composite variability index (CVI). CVI is an EEG-derived measure based on a weighted combination of BIS and estimated electromyographic activity. By assessing the relationship between these indices for equivalent levels of hypnosis (as quantified using the BIS) and the nociceptive-antinociceptive balance (as determined by the predicted effect-site concentration of remifentanil), we sought to evaluate whether combining hypnotic and analgesic measures could better predict movement in response to a noxious stimulus than when used alone. METHODS: Time series of BIS and CVI indices and the raw EEG from a previously published study were reanalyzed. In our current study, the data from 80 patients, each randomly allocated to a target hypnotic level (BIS 50 or BIS 70) and a target remifentanil level (Remi-0, -2, -4 or -6 ng/mL), were included in the analysis. CCS, CI, BIS, and CVI were calculated or quantified at baseline and at a number of intervals after the application of the Observer's Assessment of Alertness/Sedation scale and a subsequent tetanic stimulus. The dependency of the putative measures of antinociception CI and CVI on effect-site concentration of remifentanil was then quantified, together with their relationship to the hypnotic measures CCS and BIS. Finally, statistical clustering methods were used to evaluate the extent to which simple combinations of antinociceptive and hypnotic measures could better detect and predict response to stimulation. RESULTS: Before stimulation, both CI and CVI differentiated patients who received remifentanil from those who were randomly allocated to the Remi-0 group (CI: Cohen's d = 0.65, 95% confidence interval, 0.48-0.83; CVI: Cohen's d = 0.72, 95% confidence interval, 0.56-0.88). Strong correlations between BIS and CCS were found (at different periods: 0.55 < R2 < 0.68, P < 0.001). Application of the Observer's Assessment of Alertness/Sedation stimulus was associated with changes in CI and CCS, whereas, subsequent to the application of both stimuli, changes in all measures were seen. Pairwise combinations of CI and CCS showed higher sensitivity in detecting response to stimulation than CVI and BIS combined (sensitivity [99% confidence interval], 75.8% [52.7%-98.8%] vs 42% [15.4%-68.5%], P = 0.006), with specificity for CI and CCS approaching significance (52% [34.7%-69.3%] vs 24% [9.1%-38.9%], P = 0.0159). CONCLUSIONS: Combining electroencephalographically derived hypnotic and analgesic quantifiers may enable better prediction of patients who are likely to respond to tetanic stimulation.