Can use of frontal EEG monitoring increase intraoperative connected consciousness?

In this issue of the British Journal of Anaesthesia, Linassi and colleagues1Linassi F. Zanatta P. Tellaroli P. Ori C. Carron M. Isolated forearm technique: a meta-analysis to compare connected consciousness during different anaesthesia regimens.Br J Anaesth. 2018; 121: 198-209Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar have extensively reviewed and conducted a meta-analysis of the literature on the isolated forearm technique (IFT). We have great interest in this topic but avoided meta-analysis in our earlier work because of concerns over the heterogeneity in anaesthesia techniques that perhaps do not reflect routine practice.2Sanders R.D. Tononi G. Laureys S. Sleigh J.W. Unresponsiveness ≠ unconsciousness.Anesthesiology. 2012; 116: 946-959Crossref PubMed Scopus (277) Google Scholar Nonetheless, amongst other interesting observations, provocative messages are provided that frontal EEG monitoring (referred to as anaesthesia brain monitoring, ABM) and i.v. anaesthesia might be associated with increased rates of IFT responsiveness indicating intraoperative awareness (what we refer to ‘connected consciousness’ for scientific clarity). Connected consciousness2Sanders R.D. Tononi G. Laureys S. Sleigh J.W. Unresponsiveness ≠ unconsciousness.Anesthesiology. 2012; 116: 946-959Crossref PubMed Scopus (277) Google Scholar is a term used to define clinically relevant consciousness under anesthesia,3Rowley P. Boncyk C. Gaskell A. et al.What do people expect of general anaesthesia?.Br J Anaesth. 2017; 118: 486-488Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar that is, consciousness connected to the external world (and hence different to dreaming or disconnected consciousness that may also be identified by an EEG monitor). In this editorial, we explore some caveats to Linassi and colleague's1Linassi F. Zanatta P. Tellaroli P. Ori C. Carron M. Isolated forearm technique: a meta-analysis to compare connected consciousness during different anaesthesia regimens.Br J Anaesth. 2018; 121: 198-209Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar observations, referring the reader to important facets of the parent studies that influence the interpretation, but also explore the biological plausibility for the finding that titration of anaesthesia to the frontal EEG could lead to inappropriate dosing and inadvertent awareness. With regard to interpretation of the meta-analysis, the significant heterogeneity and low quality of the studies is acknowledged by the authors. Few of the data came from randomised trials. The systematic variation in anaesthetic conduct between inhalation and i.v. anaesthetic groups, and the ABM guided and non-ABM groups, undermines a key assumption of meta-analysis; namely that any observed heterogeneity is due primarily to random variation. For example, the ABM-guided subgroup contains just four studies, which were all designed with the purpose of seeing whether ABMs could detect IFT responses. To answer this question, the anaesthetic regimes were manipulated to promote IFT responses. The three studies by Russell4Russell I.F. The Narcotrend ‘depth of anaesthesia’ monitor cannot reliably detect consciousness during general anaesthesia: an investigation using the isolated forearm technique.Br J Anaesth. 2006; 96: 346-352Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 5Russell I.F. The ability of bispectral index to detect intra-operative wakefulness during isoflurane/air anaesthesia, compared with the isolated forearm technique.Anaesthesia. 2013; 68: 1010-1020Crossref PubMed Scopus (33) Google Scholar, 6Russell I.F. The ability of bispectral index to detect intra-operative wakefulness during total intravenous anaesthesia compared with the isolated forearm technique.Anaesthesia. 2013; 68: 502-511Crossref PubMed Scopus (41) Google Scholar were not classified as light anaesthesia by the authors, because the ABM targets used were within the manufacturers' recommended ‘clinical range’ (albeit at the upper extreme). However, many of the IFT responses occurred at low concentrations of anaesthetic agents (for example 0.3 vol% isoflurane). These doses are unlikely to be reflective of standard anaesthetic practice. Furthermore, the study by Kerssens and colleagues7Kerssens C. Klein J. Bonke B. Awareness: monitoring versus remembering what happened.Anesthesiology. 2003; 99: 570-575Crossref PubMed Scopus (50) Google Scholar targeted a bispectral index range of 60–70, and was self-described as a study of deep sedation rather than of general anaesthesia. It is therefore unsurprising that this group of studies yields an alarmingly high incidence of IFT responses. The high rate of explicit recall—more than two orders of magnitude greater than that typically quoted for general anaesthesia—in the ABM-guided group, is similarly testament to the light anaesthetic techniques used. Similar criticisms can be made of the finding that i.v. anaesthesia was associated with higher rates of IFT responsiveness than inhalation anaesthesia. It is worth noting that in our recent cohort study, IFT responsiveness during induction did not differ between the i.v. and inhalation anaesthetic groups.8Sanders R.D. Gaskell A. Raz A. et al.Incidence of connected consciousness after tracheal intubation: a prospective, international, multicenter cohort study of the isolated forearm technique.Anesthesiology. 2017; 126: 214-222Crossref PubMed Scopus (66) Google Scholar It is our opinion that the data presented cannot be taken to infer that type of anaesthetic or use of ABM-guidance causes unintended episodes of consciousness during routine anaesthesia care. Nonetheless we do think it is worth highlighting that these studies warrant further inspection as part of a mounting body of documented episodes of connected consciousness occurring despite seemingly acceptable frontal EEG monitor index values. Any potential awareness risk associated with the use of ABMs to titrate anaesthesia is likely to be dependent upon the manner in which they are used by clinicians. For example, as an adjunct to standard anaesthesia practice, prompting changes in anaesthetic dose at the extremes of typically observed index values, one would not expect the use of ABMs to lead to harm. However, use of ABMs to safeguard against awareness in the context of active attempts to markedly reduce hypnotic dose could constitute a clinical risk, given the demonstrated low sensitivity of ABM index values in detecting episodes of connected consciousness.4Russell I.F. The Narcotrend ‘depth of anaesthesia’ monitor cannot reliably detect consciousness during general anaesthesia: an investigation using the isolated forearm technique.Br J Anaesth. 2006; 96: 346-352Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 5Russell I.F. The ability of bispectral index to detect intra-operative wakefulness during isoflurane/air anaesthesia, compared with the isolated forearm technique.Anaesthesia. 2013; 68: 1010-1020Crossref PubMed Scopus (33) Google Scholar, 6Russell I.F. The ability of bispectral index to detect intra-operative wakefulness during total intravenous anaesthesia compared with the isolated forearm technique.Anaesthesia. 2013; 68: 502-511Crossref PubMed Scopus (41) Google Scholar, 8Sanders R.D. Gaskell A. Raz A. et al.Incidence of connected consciousness after tracheal intubation: a prospective, international, multicenter cohort study of the isolated forearm technique.Anesthesiology. 2017; 126: 214-222Crossref PubMed Scopus (66) Google Scholar, 9Gaskell A.L. Hight D.F. Winders J. et al.Frontal alpha-delta EEG does not preclude volitional response during anaesthesia: prospective cohort study of the isolated forearm technique.Br J Anaesth. 2017; 119: 664-673Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 10Zand F. Hadavi S.M. Chohedri A. Sabetian P. Survey on the adequacy of depth of anaesthesia with bispectral index and isolated forearm technique in elective Caesarean section under general anaesthesia with sevoflurane.Br J Anaesth. 2014; 112: 871-878Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar These concerns need to be addressed with carefully designed prospective controlled studies involving real-time assessment of consciousness. Recently, we attempted to identify candidate frontal EEG biomarkers of the conscious state from a subgroup of the ConsCIOUS study without success. We also did not find evidence that use of an ABM was associated with increased connected consciousness, although it may be argued that the study was underpowered for this endpoint (83% of responders vs 58% of non-responders had an ABM; P=0.13).8Sanders R.D. Gaskell A. Raz A. et al.Incidence of connected consciousness after tracheal intubation: a prospective, international, multicenter cohort study of the isolated forearm technique.Anesthesiology. 2017; 126: 214-222Crossref PubMed Scopus (66) Google Scholar However, in order to ascribe causation to the association of ABM and IFT responsiveness, one would need to know that anaesthetic dosing was titrated to the ABM, something that can be difficult in the induction period that we studied. It is worth noting that ABM values were generally higher in responders than in non-responders, indicating some population level effect.8Sanders R.D. Gaskell A. Raz A. et al.Incidence of connected consciousness after tracheal intubation: a prospective, international, multicenter cohort study of the isolated forearm technique.Anesthesiology. 2017; 126: 214-222Crossref PubMed Scopus (66) Google Scholar The fallacy here may be the ‘clinical range’ reported by ABM manufacturers. None of these ranges have been shown to be adequate for preventing intraoperative awareness, with more recent studies relying on explicit recall as a surrogate of intraoperative events.11Avidan M.S. Jacobsohn E. Glick D. et al.Prevention of intraoperative awareness in a high-risk surgical population.New Engl J Med. 2011; 365: 591-600Crossref PubMed Scopus (395) Google Scholar, 12Mashour G.A. Shanks A. Tremper K.K. et al.Prevention of intraoperative awareness with explicit recall in an unselected surgical population: a randomized comparative effectiveness trial.Anesthesiology. 2012; 117: 717-725Crossref PubMed Scopus (189) Google Scholar, 13Myles P.S. Leslie K. McNeil J. Forbes A. Chan M.T. Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial.Lancet. 2004; 363: 1757-1763Abstract Full Text Full Text PDF PubMed Scopus (910) Google Scholar Perhaps it is time to re-evaluate the ABM ‘clinical range’ as a guide to anaesthetic management. A more controversial view is that it could be considered unwise to titrate anaesthetic drugs to the activity of a brain region that might not be necessary for consciousness, such as the prefrontal cortex.14Sanders R.D. Mostert N. Lindroth H. Tononi G. Sleigh J. Is consciousness frontal? Two perioperative case reports that challenge that concept.Br J Anaesth. 2018; 121: 330-332Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 15Boly M. Massimini M. Tsuchiya N. Postle B.R. Koch C. Tononi G. Are the neural correlates of consciousness in the front or in the back of the cerebral cortex? Clinical and neuroimaging evidence.J Neurosci. 2017; 37: 9603-9613Crossref PubMed Scopus (216) Google Scholar While prefrontal cortex has an important role in higher order cognition, such as executive function, its role in arguably more primitive functions, such as consciousness, appears less absolute. It is conceivable that titration of the anaesthetic to the frontal EEG could provide a false sense of security about the probability of connected consciousness. Prefrontal cortex might not be part of the minimum neural correlates for connected consciousness (as has recently been described for disconnected consciousness in sleep).16Siclari F. Baird B. Perogamvros L. et al.The neural correlates of dreaming.Nat Neurosci. 2017; 20: 872-878Crossref PubMed Scopus (298) Google Scholar In the context of recent concerns about overly deep anaesthesia,17Maheshwari A. McCormick P.J. Sessler D.I. et al.Prolonged concurrent hypotension and low bispectral index (‘double low’) are associated with mortality, serious complications, and prolonged hospitalization after cardiac surgery.Br J Anaesth. 2017; 119: 40-49Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar it is further conceivable that titration of anaesthesia to a lighter plane, based on an ABM, might increase intraoperative connected consciousness, especially in younger people. Based on the caveats above, we argue that (i) further mechanistic work is required to identify a robust marker of connected consciousness under anaesthesia based on a priori defined statistical requirements for performance, and (ii) thereafter an adequately powered randomised controlled trial of ABM would be required to demonstrate whether use of an ABM can alter the rate of intraoperative connected consciousness. In the meantime, we do not advocate that frontal EEG monitoring is abandoned but highlight the limitations of current monitors and caution that minimising hypnotic concentrations based on the advertised ‘clinical range’ might not be prudent in all patients. Wrote the first draft of the paper with input from J.S: R.D.S., A.G. R.D.S. is a member of the editorial board of the British Journal of Anaesthesia and J.S. is an associate editor of Anesthesiology.