See Article, page 973

In this Pro-Con commentary article, the authors have been asked to support or refute a position regarding the use of processed electroencephalography (pEEG) during anesthesia to reduce postoperative delirium (POD). POD is a perioperative neurocognitive disorder that manifests acutely with deficiencies in attention and cognition.1 It is prevalent in older adults after surgery and is associated with increased mortality, functional impairment, and increased lengths of stay,2 as well as accelerated and persistent cognitive decline.3,4 As a potentially preventable condition, POD is an attractive public health target to minimize the increasing burden on patients and health care expenditures.5–7

pEEG monitors are marketed as supplemental clinical tools to aid in monitoring anesthetic depth.8 The most commonly used is the bispectral index (BIS) monitor (Medtronic/Covidien), which generates a dimensionless number ranging from 0 to 100 using a proprietary algorithm.9 The optimal application and efficacy of pEEG guidance to reduce POD is controversial and has been subject to multiple systematic reviews and meta-analyses.10–13 This Pro-Con debate provides insights into current perspectives on EEG guidance in reducing POD.

PRO: EEG SHOULD BE USED TO REDUCE POSTOPERATIVE DELIRIUM David Hao and Daniel Saddawi-Konefka

The relationship between processed EEG and POD has been scrutinized, often with varying conclusions as the evidence base has evolved.10–13 Initial interest in pEEG was supported by a number of trials14–16 and 2 systematic reviews and meta-analyses.10,11 The first systematic review found a reduced risk of POD within 7 days after surgery with a risk ratio (RR) of 0.71,10 and the second found a 38% odds reduction for POD (odds ratio [OR], 0.62).11 Based on these initial trials and reviews, there was understandable excitement about using pEEG to decrease POD, and such recommendations were included in several guidelines.17–19

This initial enthusiasm was tempered for some by the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) trial.20 The ENGAGES trial was a single-center, prospective, randomized controlled trial (RCT) designed to investigate whether decreasing EEG suppression during general anesthesia, compared with usual care, reduced the incidence of POD on postoperative days 1 to 5 in patients >60 years of age undergoing noncardiac surgery. The trial failed to show a difference between groups. Delirium occurred in 157 of 604 patients (26%) in the EEG-guided group and 140 of 609 patients (23%) in the usual care group (difference, 3.0%; 95% confidence interval [CI], −2.0 to 8.0; P = .22).

After ENGAGES was published in 2019, another large prospective trial assessing the impact on EEG-guided anesthetic depth on POD was published.21 This was a substudy of the Balanced study, a multicenter, prospective randomized trial of 655 at-risk patients from 8 centers across 3 countries. In this POD trial, patients were assigned to light anesthesia (target BIS, 50) versus deep anesthesia (target BIS, 35), and the primary outcome was delirium within the first 5 postoperative days. Consistent with trials conducted before ENGAGES, the incidence of POD was significantly lower in the light anesthesia group that that in the deep anesthesia group (19% vs 28%; OR, 0.58; 95% CI, 0.38–0.88).

To help reconcile these differences, an updated meta-analysis that included both trials was conducted by Sumner et al.13 Nine RCTs comprising 4648 eligible subjects were included. When considering all eligible trials, investigators found a nonsignificant difference between groups. The incidence of POD in the light anesthesia or EEG-guided group was 19% compared with 23.3% in the deep anesthesia or usual care group (pooled OR, 0.78; 95% CI, 0.60–1.00). The authors noted that their analysis was limited by significant heterogeneity between studies. Even more interestingly, exclusion of a single RCT (the ENGAGES trial) reduced the statistical heterogeneity to 0 and resulted in a statistically significant reduction in POD for patients in the light anesthesia or EEG-guided group (OR, 0.65; 95% CI, 0.55–0.77; P < .0001).

To understand why the ENGAGES trial, although well planned and executed, is so at odds with the preponderance of evidence in this space, we need to consider the details and limitations of the trial. First, we would be remiss if we did not mention that in the ENGAGES trial, POD was only assessed once daily, and the earliest assessment of delirium was not until after 1:00 pm on postoperative day 1. Because of this, it is likely that investigators missed clinically significant episodes of delirium, which may occur sooner postoperatively. That aside, there are other meaningful issues. In the ENGAGES trial, investigators counseled clinicians to decrease anesthetic administration primarily in response to EEG suppression. Alhough there was a statistically significant decrease in EEG suppression in the intervention group compared with the control group (median of 7 minutes versus 13 minutes), the 7 minutes that the intervention group spent in suppression is still substantial. Previous work conducted at the same institution where ENGAGES was performed suggests that 7 minutes of suppression may have been above a suppression threshold associated with increased delirium incidence.22 This claim is supported by the fact that the intervention group also spent a large amount of time with BIS values <40 (a median of 32 minutes). It must be emphasized that this is substantially more time with deep anesthesia than in other EEG studies for POD prevention. For example, in the Cognitive Dysfunction after Anesthesia (CODA) trial,14 patients in the intervention group spent a median time of only 6.9 minutes with BIS values <40. In fact, even patients in the control group of the CODA trial spent less time with BIS values <40 (median 25.7 minutes) than the intervention group of ENGAGES. It is postulated that a threshold effect exists with respect to the time spent in suppression or with low BIS that may predispose to adverse cognitive outcomes.23

Taken together, these factors suggest that the intervention in the ENGAGES trial was inadequate in producing meaningfully lighter anesthesia. Put another way, clinicians who are interested in decreasing POD using pEEG should not use the intervention as designed and executed in ENGAGES. With any monitor, it is ultimately the clinician’s response to the information derived that is important in answering the question of the inherent value of a monitor.24 This is elegantly considered in Sumner’s meta-analysis. By analyzing the subset of studies (4 RCTs) that reported data only from trials that adhered to manufacturer instructions and published guidelines for the target range of the relevant pEEG device, Sumner et al13 found a large and significant reduction in POD with pEEG-guided general anesthesia (OR, 0.57; 95% CI, 0.45–0.74; P < .0001). As the authors note, it is likely how clinicians use data derived from the monitor that ultimately leads to the reduction in POD incidence.

In summary, the totality of the current state of the literature suggests a benefit to pEEG guidance with general anesthesia in reducing the incidence of POD. The ENGAGES trial is the outlier in its outcome, but the information gleaned from the study is invaluable. It suggests that there may be a threshold of anesthesia depth beyond which titration is ineffective for reducing POD. Based on this, clinicians who wish to minimize POD must target lighter depths of anesthesia (DOAs).

CON: EEG SHOULD NOT BE USED TO REDUCE POSTOPERATIVE DELIRIUM Bradley Fritz and Ben Julian A. Palanca

The Pro argument contends that POD risk can be mitigated through minimizing pEEG DOA measures that suggest excessively deep levels of anesthesia. Such approaches assume that a causal relationship exists between excessive anesthesia exposure or certain states of anesthetic-induced unconsciousness and POD. A second assumption is that the risks associated with anesthetic downtitration do not outweigh the potential benefits. Finally, a third assumption is that the appropriate EEG targets to guide anesthetic titration are known. We have concerns regarding all 3 of these assumptions.

First, the current body of literature does not provide sufficient evidence to claim that a causal relationship exists between anesthetic depth and POD. From a pathophysiologic standpoint, the mechanistic pathways whereby intravenous or inhaled anesthetics would contribute to neural dysfunction underlying delirium, from molecular to neural systems level, have not been established. Arguably, the lack of an established animal model for elucidating delirium pathophysiology is contributory. However, even a recent RCT of general anesthesia versus regional anesthesia without sedation in geriatric patients undergoing hip fracture surgery reported no significant difference in POD.25 Thus, the premise of general anesthesia, and thus anesthetic depth, as a major modifiable contributor to POD should be considered cautiously. Furthermore, the association between EEG burst suppression and POD was described in 2 single-center prospective cohort studies.22,26 Because these were observational studies, one should not infer causality from the findings. The ideal way to test for a causal relationship would be to randomize patients to experience burst suppression or not experience burst suppression during surgery. Such studies are impossible because the EEG is not entirely under the anesthesia clinician’s direct control. Although clinicians can impact the EEG through titration of either intravenous or inhalational agents, the dose-response relationship is highly variable across patients. To overcome this limitation, statistical mediation analysis is commonly used in observational data to determine whether one variable is likely to lie along a causal pathway between 2 other variables. Pedemonte et al27 reported that among cardiac surgical patients, burst suppression during cardiopulmonary bypass mediated the relationships of physical function, on-pump temperature, and prebypass EEG alpha power on POD. However, the authors commented that the results should be considered exploratory because the analyses were not prespecified.28,29 In a prespecified secondary analysis of the ENGAGES trial, a small proportion of the effect of preoperative cognitive abnormality on POD was mediated by intraoperative burst suppression.30 Although it would seem logical to test whether burst suppression lies along a causal pathway between anesthetic exposure (perhaps quantified as end-tidal anesthetic concentration) and POD, such a theoretical model violates the assumptions of mediation analysis because increased end-tidal anesthetic concentration is not generally associated with increased risk of POD. On the contrary, patients who exhibit burst suppression at low anesthetic concentrations seem to have a higher incidence of POD.31,32 Based on the available data, it remains unclear whether there is a causal relationship between intraoperative burst suppression and POD.

Second, if anesthetic agents are to be downtitrated to prevent POD, then there may be an increased risk of insufficient anesthetic administration. The potential benefits of reduced anesthesia levels must be weighed against the risks of insufficient anesthetic administration. Insufficient anesthetic administration can lead to intraoperative awareness with recall, a distressing condition that occurs in 1 to 2 anesthetics per thousand. Awareness with recall can lead to posttraumatic stress disorder, especially if the patient has been paralyzed with neuromuscular blocking agents.33 Both the Balanced Anesthesia Trial and the ENGAGES trial reported awareness outcomes alongside the other trial results,20,34 whereas the CODA trial did not present data on awareness.14 In the Balanced trial, there was 1 case of awareness with recall among 3316 patients in the BIS 50 group, and there were no cases of awareness among 3328 patients in the BIS 35 group.34 This difference was not statistically significant. In ENGAGES, there were no cases of awareness with recall in either the EEG-guided group or the usual care group.20 However, there was a significantly higher incidence of undesirable intraoperative movement in the EEG-guided group compared with the usual care group. Although none of the patients who exhibited intraoperative movement went on to develop awareness with recall, it is unknown whether some of these episodes represented awareness without recall. Furthermore, the risks of both unanticipated intraoperative movement and treatment need to be considered.

Finally, even if deep anesthesia causes POD and the benefits of anesthetic downtitration outweigh the benefits, the most appropriate EEG signatures to guide anesthetic titration are not known. Most investigators and clinicians rely upon the BIS or other pEEG DOA monitors due to their widespread availability and ease of use. However, BIS is not a perfect correlate for unconsciousness, especially if the numeric value is utilized without examining the raw EEG waveform. BIS readings may be artifactually elevated by common exposures such as nearby electrocautery,35 train-of-four monitoring,36 and forced-air warming devices.37,38 In addition, paradoxical increases in BIS values after ketamine administration have been documented.39,40 Furthermore, BIS may be very sensitive to neuromuscular blocking agents. In a study of 10 healthy volunteers, BIS readings decreased to the 40s after administration of suxamethonium and rocuronium without the concurrent administration of sedative agents.39 All participants reported being fully aware throughout the entire experiment. In a different study of patients undergoing propofol/remifentanil anesthesia with rocuronium use, BIS readings increased by >10 points after either sugammadex or neostigmine administration if electromyelographic (EMG) activity increased substantially at the time of rocuronium reversal.41

Even using raw EEG waveforms rather than pEEG values, it remains unclear what EEG patterns can serve as reliable indicators of unconsciousness. When using frontal EEG channels, slow delta waves with superimposed alpha oscillations have been thought to strongly indicate that a patient will not respond to external stimuli.42 However, a multicenter prospective cohort study produced evidence that contradicts this notion. In this study, 12 of 260 patients (4.6%) undergoing general anesthesia with endotracheal intubation exhibited connected consciousness after intubation, as demonstrated with the isolated forearm technique.43 In a substudy examining EEG waveforms among participants at 3 centers, 3 of 6 patients with connected consciousness displayed an alpha-delta frontal EEG pattern at the time they were following commands.44 Such an observation runs contrary to the expectation of delta oscillations (<4 Hz), serving as a reliable intraoperative EEG marker of unconsciousness. Thus, analysis of the raw EEG waveform alone may be insufficient to ensure that patients remain adequately anesthetized during surgery.

Based on the lack of an established causal relationship between deep anesthesia and POD, the risks associated with insufficient anesthetic administration, and the lack of reliable EEG correlates for unconsciousness, we do not feel there is sufficient evidence to recommend EEG-guided titration of anesthesia to solely prevent POD. And we are not alone in this opinion. In a 2020 joint consensus statement, the American Society for Enhanced Recovery and the Perioperative Quality Initiative concluded that “there is insufficient evidence to recommend using processed EEG monitoring in older high-risk surgical patients undergoing general anesthesia to reduce the risk of POD.”45 Lack of adequate evidence is not evidence for lack of benefit, but at this time, the lack of evidence persists.

PRO: REJOINDER

Although the arguments presented by the Con side are compelling, they are incomplete. First, our colleagues state that the mechanisms by which exposure to anesthetic agents might lead to POD are not known. Although we agree the mechanisms have not been fully elucidated, lack of a full mechanistic understanding does not mean that well-documented clinical relationships should be ignored. For example, volatile agents continue to be used for general anesthesia even though their mechanism of action remains incompletely understood >175 years after their first empiric use.

Second, our colleagues cite several observational studies to claim that a causal relationship between anesthetic depth and POD has not been established. Although the cited studies applied sophisticated statistical techniques to investigate possible mediation relationships among variables, the evidence provided by observational studies will always be weaker than the evidence provided by interventional investigations, particularly RCTs. Given that multiple trials randomizing patients to lighter or deeper anesthesia have been published, decision-making should be based primarily on interpretation of those randomized trials, rather than observational studies.

Our colleagues also claim that targeting lighter anesthesia may introduce unacceptable risks. With regard to awareness after general anesthesia, this claim is unfounded, as no published trial has reported a statistically significant difference in awareness between patients randomized to lighter anesthesia and patients randomized to deeper anesthesia. Furthermore, the protocols in the “lighter” anesthesia arms of the published trials have consistently targeted values that have demonstrated reduced intraoperative awareness when compared with usual care with no intervention46 and similar risk compared with end-tidal anesthetic concentration monitoring.9,47,48 That there may be increased movement at lower anesthetic depth doses does not mean that pEEG use is ineffective for reduction of POD. Rather, it highlights the tradeoffs that must be considered for all clinical decisions.

Finally, we agree that the precise pEEG signatures to target remain unfocused. However, as we presented in our Pro side, targeting substantially lighter planes of anethesia (eg, BIS >40) has been empirically shown to decrease risk of POD. This sort of target should not be ignored until precise signatures are fully elucidated. For all these reasons, we believe the arguments made by the Con side should be considered with caution.

CON: REJOINDER

The argument that the authors of the Pro side put forward hinges on ENGAGES being a flawed trial. They note that when ENGAGES is excluded, and only other trials are examined, a small signal appears in favor of EEG reducing POD. They contend that the ENGAGES trial is an aberration in the overall direction of the body of evidence. One persistent detraction cited about the trial is that the intervention was inadequate in producing meaningfully lighter anesthesia. However, this concern was specifically addressed by 3 post hoc sensitivity analyses conducted as part of ENGAGES. Even with exclusion of patients in the EEG-guided group with the most EEG suppression, most time with BIS <40, and highest volatile anesthetic concentrations, no significant difference in POD incidence was observed.

Table. - Pro-Con Debate Summary PRO side: arguments in favor of EEG for POD Large reduction in POD with pEEG-guided general anesthesia when considering trials that adhered to manufacturer instructions and guidelines for target pEEG ranges Intervention group in ENGAGES did not achieve meaningful lighter anesthesia (significant time spent by both groups in suppression) Anesthetic depth threshold beyond which titration is ineffective for reducing POD may exist CON side: arguments against EEG for POD Lack of evidence that associations between anesthetic depth and POD represent causal relationships Unclear whether potential benefits of reduced anesthesia levels outweigh risks of potentially insufficient anesthetic administration The most appropriate EEG signatures to guide anesthetic titration remain unknown

Abbreviations: EEG, electroencephalography; ENGAGES, Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes; pEEG, processed electroencephalography; POD, postoperative delirium.

All trials have flaws, and to exclude the largest trial that specifically addresses this question is arbitrary at best. They reference the recent meta-analysis by Sumner et al. Notably, the primary analysis in that publication resulted in a nonsignificant difference between groups. It is only through an exploratory subgroup analysis or exclusion of the ENGAGES trial that a statistically significant benefit to using pEEG-guided general anesthesia or a lighter pEEG target is seen. Although the ENGAGES trial may have some flaws, it remains the largest RCT to date evaluating the effect of EEG-guided anesthesia administration on POD. To categorically disregard the study or to exclude it from a meta-analysis is contradictory to the iterative process of generating evidence.

SUMMARY

This Pro-Con article was prompted by the recognition that anesthesia clinicians will be increasingly responsible for considering interventions to prevent POD. POD is a public health priority, and anesthesia clinicians should familiarize themselves with potential strategies to decrease the incidence of POD. We have presented arguments for and against the use of EEG in preventing POD (Table). The consensus opinion of the authors is that the status of the literature is limited by marked heterogeneity, including the study populations, interventions delivered, and outcome measurements. Further research should explore the most appropriate EEG signatures to guide anesthetic titration and further refine understanding of the relationship between anesthetic depth and POD.

DISCLOSURES

Name: David Hao, MD.

Contribution: This author helped conceive and construct the Pro side.

Name: Bradley Fritz, MD, MSCI.

Contribution: This author helped conceive and construct the Con side.

Name: Daniel Saddawi-Konefka, MD, MBA.

Contribution: This author helped conceive and construct the Pro side.

Name: Ben J. Palanca, MD, PhD.

Contribution: This author helped conceive and construct the Con side.

This manuscript was handled by: Oluwaseun Johnson-Akeju, MD, MMSc.

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