Three blind mice: a tail of discordant trials
2019; Elsevier BV; Volume: 124; Issue: 2 Linguagem: Inglês
10.1016/j.bja.2019.09.035
ISSN1471-6771
AutoresElizabeth L. Whitlock, Michael S. Avidan,
Tópico(s)Intensive Care Unit Cognitive Disorders
ResumoIn their recently published white paper, 'State of the clinical science of perioperative brain health: report from the American Society of Anesthesiologists Brain Health Initiative Summit 2018', Mahanna-Gabrielli and colleagues1Mahanna-Gabrielli E. Schenning K.J. Eriksson L.I. et al.State of the clinical science of perioperative brain health: report from the American society of Anesthesiologists brain health initiative Summit 2018.Br J Anaesth. 2019; 123: 464-478Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar charted a valuable map on perioperative brain health for anaesthesiology. One of the areas addressed in the white paper is the potential of EEG and processed EEG guidance of general anaesthesia to prevent postoperative delirium and other neurocognitive disorders. The most commonly used processed EEG monitor is the bispectral index (BIS™) monitor (Medtronic, Minneapolis, MN, USA). The BIS uses a proprietary algorithm to analyse the EEG signal to provide a single dimensionless number from 0 to 100 to indicate depth of anaesthesia; readings between 40 and 60 are intended to reflect an appropriate hypnotic component of general anaesthesia. The notable limitations of the BIS have been described,2Whitlock E.L. Villafranca A.J. Lin N. et al.Relationship between bispectral index values and volatile anesthetic concentrations during the maintenance phase of anesthesia in the B-Unaware trial.Anesthesiology. 2011; 115: 1209-1218Crossref PubMed Scopus (98) Google Scholar, 3Schuller P.J. Newell S. Strickland P.A. Barry J.J. Response of bispectral index to neuromuscular block in awake volunteers.Br J Anaesth. 2015; 115: i95-i103Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 4Ni K. Cooter M. Gupta D.K. et al.Paradox of age: older patients receive higher age-adjusted minimum alveolar concentration fractions of volatile anaesthetics yet display higher bispectral index values.Br J Anaesth. 2019; 123: 288-297Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar which probably also apply to other processed EEG monitors. For these and other reasons, processed EEG monitors have generated controversy amongst anaesthetists, with some arguing strongly for their utility, and others viewing them as having questionable value in relation to anaesthetic management. Notwithstanding their limitations, the roles of EEG and processed EEG indices have received attention for their theoretical ability to optimise anaesthetic dosing according to individual needs, with possible clinical benefits. In a recent 'best practices' document, it was stated that 'EEG-based anaesthetic titration has been shown to lower delirium and postoperative cognitive dysfunction (POCD) rates in multiple independent randomised controlled trials (i.e., level 1 evidence)'.5Berger M. Schenning K.J. Brown C.H. et al.Best practices for postoperative brain health: recommendations from the fifth international perioperative neurotoxicity working group.Anesth Analg. 2018; 127: 1406-1413Crossref PubMed Scopus (114) Google Scholar According to the strength of this implied recommendation,6Burns P.B. Rohrich R.J. Chung K.C. The levels of evidence and their role in evidence-based medicine.Plast Reconstr Surg. 2011; 128: 305-310Crossref PubMed Scopus (1003) Google Scholar the overwhelming majority of UK anaesthetists are non-compliant with best practice, because they are not using EEG- or processed EEG-based anaesthetic titration.7Kemp H. Marinho S. Cook T.M. et al.An observational national study of anaesthetic workload and seniority across the working week and weekend in the UK in 2016: the 6th National Audit Project (NAP6) Activity Survey.Br J Anaesth. 2018; 121: 134-145Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar In view of the limited adoption of EEG-guided anaesthesia in the UK and possibly elsewhere, and the potential clinical and financial ramifications of using this technology widely to prevent delirium and other neurocognitive disorders, it is important to evaluate critically the strengths and weaknesses of existing evidence from randomised trials. Three large published trials have examined the role of BIS- or EEG-guided anaesthesia in preventing neurocognitive disorders in broad surgical populations.8Chan M.T. Cheng B.C. Lee T.M. Gin T. CODA Trial GroupBIS-guided anesthesia decreases postoperative delirium and cognitive decline.J Neurosurg Anesthesiol. 2013; 25: 33-42Crossref PubMed Scopus (464) Google Scholar, 9Radtke F.M. Franck M. Lendner J. Kruger S. Wernecke K.D. Spies C.D. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.Br J Anaesth. 2013; 110: i98-i105Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar, 10Wildes T.S. Mickle A.M. Ben Abdallah A. et al.Effect of electroencephalography-guided anesthetic administration on postoperative delirium among older adults undergoing major surgery: the ENGAGES randomized clinical trial.JAMA. 2019; 321: 473-483Crossref PubMed Scopus (203) Google Scholar Mahanna-Gabrielli and colleagues1Mahanna-Gabrielli E. Schenning K.J. Eriksson L.I. et al.State of the clinical science of perioperative brain health: report from the American society of Anesthesiologists brain health initiative Summit 2018.Br J Anaesth. 2019; 123: 464-478Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar discussed two of these (CODA8Chan M.T. Cheng B.C. Lee T.M. Gin T. CODA Trial GroupBIS-guided anesthesia decreases postoperative delirium and cognitive decline.J Neurosurg Anesthesiol. 2013; 25: 33-42Crossref PubMed Scopus (464) Google Scholar and ENGAGES10Wildes T.S. Mickle A.M. Ben Abdallah A. et al.Effect of electroencephalography-guided anesthetic administration on postoperative delirium among older adults undergoing major surgery: the ENGAGES randomized clinical trial.JAMA. 2019; 321: 473-483Crossref PubMed Scopus (203) Google Scholar); the SuDoCo trial9Radtke F.M. Franck M. Lendner J. Kruger S. Wernecke K.D. Spies C.D. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.Br J Anaesth. 2013; 110: i98-i105Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar was not addressed. They described the pathway by which EEG-based monitors, such as the BIS, are hypothesised to prevent delirium: minimising excessive anaesthesia and decreasing time spent with EEG suppression or low BIS readings (i.e. BIS 0.35 minimum alveolar concentration [MAC]),8Chan M.T. Cheng B.C. Lee T.M. Gin T. CODA Trial GroupBIS-guided anesthesia decreases postoperative delirium and cognitive decline.J Neurosurg Anesthesiol. 2013; 25: 33-42Crossref PubMed Scopus (464) Google Scholar from which less suppression time and higher BIS readings might be expected, could be required to have a measurable positive impact on postoperative delirium incidence. At first blush, this might seem reasonable. In this editorial, we enlarge on a discussion in a recent narrative review article,11Vlisides P. Avidan M. Recent advances in preventing and managing postoperative delirium.F1000Res. 2019; 8: 607Crossref Scopus (34) Google Scholar and examine more closely some of the limitations associated with the aforementioned three clinical trials.8Chan M.T. Cheng B.C. Lee T.M. Gin T. CODA Trial GroupBIS-guided anesthesia decreases postoperative delirium and cognitive decline.J Neurosurg Anesthesiol. 2013; 25: 33-42Crossref PubMed Scopus (464) Google Scholar, 9Radtke F.M. Franck M. Lendner J. Kruger S. Wernecke K.D. Spies C.D. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.Br J Anaesth. 2013; 110: i98-i105Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar, 10Wildes T.S. Mickle A.M. Ben Abdallah A. et al.Effect of electroencephalography-guided anesthetic administration on postoperative delirium among older adults undergoing major surgery: the ENGAGES randomized clinical trial.JAMA. 2019; 321: 473-483Crossref PubMed Scopus (203) Google Scholar Before delving into the trials, it is worth highlighting the limitations that are common to all three and to other studies using similar methods. All were conducted at one or two centres; all were affected by the variation in the use of EEG-based technology by clinicians who have different familiarities with EEG, and different prior beliefs and approaches to anaesthetic management; all required open study group allocation (lack of blinding of intervention); and all relied on a labour-intensive measurement of a clinical outcome (delirium), which is subjective even with the use of scoring frameworks. The two-centre CODA trial was the first large randomised trial of BIS guidance vs usual care that obtained delirium assessments in all participants, although it was focused on, and powered for, a primary outcome of POCD at 3 months.8Chan M.T. Cheng B.C. Lee T.M. Gin T. CODA Trial GroupBIS-guided anesthesia decreases postoperative delirium and cognitive decline.J Neurosurg Anesthesiol. 2013; 25: 33-42Crossref PubMed Scopus (464) Google Scholar Anaesthetists caring for patients in the guided group targeted a BIS reading between 40 and 60. The control group received usual care (anaesthetic drug dosing according to clinical judgement). According to the retrospective registration of the trial (CUHK_CCT00141),12Registration of the CODA trial. Available from http://www.chictr.org.cn/showprojen.aspx?proj=8831 (accessed 28 June 2019).Google Scholar the target enrolment was 1000 patients; 921 patients were enrolled. Delirium was included in the protocol as a secondary outcome. The patients were assessed for delirium every morning. It is atypical that no missing delirium assessments were reported, as in other comparable studies, postoperative delirium assessments were missing for patients who died, who were comatose on the ICU, who withdrew from the trial, or who refused to be assessed.9Radtke F.M. Franck M. Lendner J. Kruger S. Wernecke K.D. Spies C.D. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.Br J Anaesth. 2013; 110: i98-i105Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar,10Wildes T.S. Mickle A.M. Ben Abdallah A. et al.Effect of electroencephalography-guided anesthetic administration on postoperative delirium among older adults undergoing major surgery: the ENGAGES randomized clinical trial.JAMA. 2019; 321: 473-483Crossref PubMed Scopus (203) Google Scholar,13Avidan M.S. Maybrier H.R. Abdallah A.B. et al.Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial.Lancet. 2017; 390: 267-275Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar The median average BIS was 36 in the control group and 53 in the guided group,8Chan M.T. Cheng B.C. Lee T.M. Gin T. CODA Trial GroupBIS-guided anesthesia decreases postoperative delirium and cognitive decline.J Neurosurg Anesthesiol. 2013; 25: 33-42Crossref PubMed Scopus (464) Google Scholar indicating that the patients were maintained in the upper part of the manufacturer's recommended range when BIS was used but in a deep state during usual care. This was concurrent with a reduction in mean end-tidal anaesthetic concentration from 0.93 (standard deviation [sd]=0.34) age- and nitrous oxide-adjusted MAC in the usual care group to 0.57 (sd=0.29) MAC in the BIS-guided group. Based on these results, and assuming a normal distribution, we can infer that, for ∼16% of the patients in the guided group, the average inhaled anaesthetic concentration across the entire case was below 0.28 MAC (1 sd below the mean), which is a concentration less than MAC awake (i.e. a MAC value at which >50% of patients respond to a verbal command absent noxious stimulation). Similarly, the 75th percentile for the average BIS reading was 57 in the guided group, such that 25% of these patients had an average BIS across the entire case of 57 or higher, in which the manufacturer recommends maintaining a BIS reading of 57 is also counter to the recommendations of the B-Aware investigators, who advised 'ensure that the BIS is less than 55 if awareness is to be avoided in most cases'.14Myles 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 The fact that the experimentalists achieved their goals of reducing anaesthetic administration and anaesthetic depth to this extent, and concurrently delirium incidence by 8.5% (or 35% relative reduction), is impressive. This raises questions regarding the trade-off between hypothetical delirium prevention and concern for iatrogenic complications, such as intraoperative awareness and consequent psychological disorders. Another arithmetic conclusion from the CODA study also raises concern about sub-hypnotic anaesthetic technique in the BIS-guided group. Roughly 90% of participants received inhaled anaesthetic agents. MAC was adjusted for both age and nitrous oxide use; the mean nitrous oxide concentration in the BIS-guided group was 63%, and more than half the patients in both groups in CODA received nitrous oxide as part of their anaesthetic. For a 60-yr-old patient, 63% nitrous oxide represents ∼0.7 MAC.15Lerou J.G. Nomogram to estimate age-related MAC.Br J Anaesth. 2004; 93: 288-291Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar As the mean age- and nitrous oxide-adjusted MAC in the BIS-guided group was 0.57, this suggests that many of the patients in the CODA trial received nitrous oxide as the sole hypnotic agent. A nitrous oxide-only anaesthetic regimen has little relevance to current practice because, except in rare clinical circumstances, it is inadequate to ensure hypnosis. However, as nitrous oxide is not reflected in EEG in the same way as GABAergic drugs, such as propofol and halogenated anaesthetics, it may explain the remarkably high BIS values in the experimental group. There are other concerns regarding the CODA trial, and we believe that these should be thoughtfully evaluated when considering the clinical applicability of its findings. (i) According to the unpublished protocol and from the appendix of the primary manuscript,8Chan M.T. Cheng B.C. Lee T.M. Gin T. CODA Trial GroupBIS-guided anesthesia decreases postoperative delirium and cognitive decline.J Neurosurg Anesthesiol. 2013; 25: 33-42Crossref PubMed Scopus (464) Google Scholar CODA was a two-centre trial, but the results by centre were not presented in the primary manuscript. Differences between centres could have confounded the results. (ii) The mean age was 68 (sd=8) yr. This suggests either that some enrolled patients were younger than the minimum required age of 60, or that the ages of participants were extremely skewed and should have been reported differently. (iii) There was reportedly a significant decrease in POCD at 3 months in the BIS-guided group, but by the Fisher's exact test (the statistical test pre-specified by the investigators to assess the primary outcome8Chan M.T. Cheng B.C. Lee T.M. Gin T. CODA Trial GroupBIS-guided anesthesia decreases postoperative delirium and cognitive decline.J Neurosurg Anesthesiol. 2013; 25: 33-42Crossref PubMed Scopus (464) Google Scholar) the unadjusted odds ratio for POCD with BIS guidance was 0.66 (95% confidence interval [CI]: 0.4353–1.0036; P=0.059). (iv) There are methodological differences amongst the unpublished protocol, the registration site, and the primary manuscript, all of which should be reliable source documents. For example, the stated sample size goal in the protocol was 900, it was 1000 on the registration site, and the manuscript stated 900. In contrast, the power calculation parameters in the protocol and the manuscript suggest that only 316 total patients (158 per group) would be needed. (v) Further, the power calculation was based on results obtained in a study by Monk and colleagues.16Monk T.G. Weldon B.C. Garvan C.W. et al.Predictors of cognitive dysfunction after major noncardiac surgery.Anesthesiology. 2008; 108: 18-30Crossref PubMed Scopus (1028) Google ScholarBut this study16 was published a year after enrolment to the CODA trial began, and found a very different incidence of POCD at 3 months after surgery (12.7%) than the incidence that was used for the power calculation in the CODA trial (30%). (vi) The mean duration of anaesthesia was only 2.05 (sd=1.05) h,8Chan M.T. Cheng B.C. Lee T.M. Gin T. CODA Trial GroupBIS-guided anesthesia decreases postoperative delirium and cognitive decline.J Neurosurg Anesthesiol. 2013; 25: 33-42Crossref PubMed Scopus (464) Google Scholar implying that the median duration of surgery was probably <2 h. This suggests that fewer than half the patients might have met the specified duration of surgery target for the trial. This is difficult to reconcile with the investigators' statement, 'Our study population was restricted to the elderly patients undergoing major surgery; therefore, the results may not be generalized to patients undergoing minor surgery with duration <2 hours'.8Chan M.T. Cheng B.C. Lee T.M. Gin T. CODA Trial GroupBIS-guided anesthesia decreases postoperative delirium and cognitive decline.J Neurosurg Anesthesiol. 2013; 25: 33-42Crossref PubMed Scopus (464) Google Scholar (vii) In contrast to the SuDoCo9Radtke F.M. Franck M. Lendner J. Kruger S. Wernecke K.D. Spies C.D. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.Br J Anaesth. 2013; 110: i98-i105Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar and ENGAGES10Wildes T.S. Mickle A.M. Ben Abdallah A. et al.Effect of electroencephalography-guided anesthetic administration on postoperative delirium among older adults undergoing major surgery: the ENGAGES randomized clinical trial.JAMA. 2019; 321: 473-483Crossref PubMed Scopus (203) Google Scholar trials, no protocol violations were reported (e.g. unblinding by clinicians in the blinded group or BIS not working in the guided group), which is unusual for such a large pragmatic trial. The SuDoCo trial was a single-centre study, which was partially funded by the manufacturer of the BIS,9Radtke F.M. Franck M. Lendner J. Kruger S. Wernecke K.D. Spies C.D. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.Br J Anaesth. 2013; 110: i98-i105Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar and was published shortly after CODA. According to the retrospective registration of the SuDoCo trial (ISRCTN36437985),17Registration of SuDoCo trial. Available from http://www.isrctn.com/ISRCTN36437985 (accessed 28 June 2019).Google Scholar the target enrolment was 1600 patients; 1277 noncardiac surgery patients were enrolled, and 1193 were treated in the two study groups: BIS guided and usual care.9Radtke F.M. Franck M. Lendner J. Kruger S. Wernecke K.D. Spies C.D. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.Br J Anaesth. 2013; 110: i98-i105Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar The study was terminated prematurely because of lack of funds. Postoperative in-hospital delirium incidence, assessed twice daily up to 1 week, was the primary outcome.17Registration of SuDoCo trial. Available from http://www.isrctn.com/ISRCTN36437985 (accessed 28 June 2019).Google Scholar Anaesthetists in one group were instructed on how to use the BIS to guide anaesthetic depth (presumably, to maintain the index between 40 and 60, although it is not explicitly stated), and always used it for their patients.9Radtke F.M. Franck M. Lendner J. Kruger S. Wernecke K.D. Spies C.D. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.Br J Anaesth. 2013; 110: i98-i105Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar Anaesthetists in the other group never used BIS, and conducted all aspects of anaesthesia according to their clinical judgement.9Radtke F.M. Franck M. Lendner J. Kruger S. Wernecke K.D. Spies C.D. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.Br J Anaesth. 2013; 110: i98-i105Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar In keeping with the CODA trial, the incidence of delirium was lower in the guided (16.5%) than in the usual care group (21.4%), with an absolute reduction of 4.9% (95% CI: 0.3–9.4%; P=0.036).9Radtke F.M. Franck M. Lendner J. Kruger S. Wernecke K.D. Spies C.D. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.Br J Anaesth. 2013; 110: i98-i105Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar This result yields a fragility index of 2;18Grolleau F. Collins G.S. Smarandache A. et al.The fragility and reliability of conclusions of anesthesia and critical care randomized trials with statistically significant findings: a systematic review.Crit Care Med. 2019; 47: 456-462Crossref PubMed Scopus (23) Google Scholar if there were two fewer patients with delirium in the usual care group and two more patients in the guided group, the P-value would be 0.052. Remarkably, in stark contrast to the CODA trial, there was an almost indistinguishable difference in BIS readings between groups: the mean average BIS for both the guided and routine care groups was 39.9Radtke F.M. Franck M. Lendner J. Kruger S. Wernecke K.D. Spies C.D. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.Br J Anaesth. 2013; 110: i98-i105Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar However, of the 13 post hoc arithmetic treatments of the study subjects' BIS readings, two achieved P<0.05 in univariate testing, unadjusted for multiple comparisons: suppression ratio and BIS <20.9Radtke F.M. Franck M. Lendner J. Kruger S. Wernecke K.D. Spies C.D. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction.Br J Anaesth. 2013; 110: i98-i105Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar The authors, therefore, hypothesised that the causal pathway between BIS guidance and lower postoperative delirium rates included the avoidance of extremely deep anaesthetic states. The major limitation of the SuDoCo trial design, in which different anaesthetists provided care to the BIS vs control patients, lends a more parsimonious explanation for the decrease in delirium, if not simply a chance 'positive' finding: that there may have been some systematic differences in perioperative management between the two groups of anaesthetists who participated. One of the authors of this editorial (MSA) was the principal investigator for the ENGAGES trial. ENGAGES was also a single-centre trial that enrolled 1232 patients who were randomised to EEG-guided anaesthesia or usual care. The primary outcome was postoperative delirium, assessed daily starting on postoperative Day 1, the study was registered prospectively,19Registration of the ENGAGES trial. Available from https://clinicaltrials.gov/ct2/show/study/NCT02241655?term=engages&rank=2 (accessed 28 June 2019).Google Scholar and the protocol was finalised before commencement of enrolment. ENGAGES was designed to explore the hypothesis generated from SuDoCo's findings, namely, that delirium reduction can be accomplished if meaningful decrements in deep hypnotic time can be achieved. Therefore, the protocol emphasised avoidance of EEG suppression and minimising time spent with BIS 1% was reduced by 46%, from 13 to 7 min in the control and guided groups, respectively, and patients in the EEG-guided group spent roughly half as much time with BIS <40 as controls.10Wildes T.S. Mickle A.M. Ben Abdallah A. et al.Effect of electroencephalography-guided anesthetic administration on postoperative delirium among older adults undergoing major surgery: the ENGAGES randomized clinical trial.JAMA. 2019; 321: 473-483Crossref PubMed Scopus (203) Google Scholar Furthermore, a 14% reduction in anaesthetic administration—from a median of 0.80–0.69 MAC—occurred. Despite these promising numbers—a small, although statistically significant, reduction in inhaled anaesthetic administration and less deep hypnotic time—the delirium incidence was 26% in the EEG-guided group and 23% in the usual care group (absolute difference: 3%; 95% CI: –2 to 8; P=0.22).10Wildes T.S. Mickle A.M. Ben Abdallah A. et al.Effect of electroencephalography-guided anesthetic administration on postoperative delirium among older adults undergoing major surgery: the ENGAGES randomized clinical trial.JAMA. 2019; 321: 473-483Crossref PubMed Scopus (203) Google Scholar There were many limitations of the ENGAGES trial,10Wildes T.S. Mickle A.M. Ben Abdallah A. et al.Effect of electroencephalography-guided anesthetic administration on postoperative delirium among older adults undergoing major surgery: the ENGAGES randomized clinical trial.JAMA. 2019; 321: 473-483Crossref PubMed Scopus (203) Google Scholar,21Ackland G.L. Pryor K.O. Electroencephalography-guided anaesthetic administration does not impact postoperative delirium among older adults undergoing major surgery: an independent discussion of the ENGAGES trial.Br J Anaesth. 2019; 123: 112-117Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 22Radtke F.M. Franck M. Spies C.D. Electroencephalography-guided anesthetic administration and postoperative delirium.JAMA. 2019; 321: 2469-2470Crossref PubMed Scopus (4) Google Scholar, 23Zolyomi A. Gerstein N.S. Petersen T.R. Electroencephalography-guided anesthetic administration and postoperative delirium.JAMA. 2019; 321: 2470Crossref PubMed Scopus (3) Google Scholar, 24Kienbaum P. Schaefer M.S. Electroencephalography-guided anesthetic administration and postoperative delirium.JAMA. 2019; 321: 2470-2471Crossref PubMed Scopus (2) Google Scholar, 25Abbott T.E.F. Pearse R.M. Depth of anesthesia and postoperative delirium.JAMA. 2019; 321: 459-460Crossref PubMed Scopus (18) Google Scholar most notably that there might not have been sufficient reduction in anaesthetic administration or EEG suppression in the guided group to produce the desired benefit. Future studies will need to clarify whether EEG guidance of anaesthesia might lead to a small decrease in postoperative delirium. It is important to view these criticisms in appropriate temporal context; of these three trials, two were published in 2013, when trial reporting standards were less exacting than today. Despite its limitations, as a first-in-class study with impressive positive findings, the CODA trial has been highly cited and has had a substantial influence on clinical practice guidelines,5Berger M. Schenning K.J. Brown C.H. et al.Best practices for postoperative brain health: recommendations from the fifth international perioperative neurotoxicity working group.Anesth Analg. 2018; 127: 1406-1413Crossref PubMed Scopus (114) Google Scholar,26American Geriatrics Society Expert Panel on Postoperative Delirium in Older AdultsAmerican Geriatrics Society abstracted clinical practice guideline for postoperative delirium in older adults.J Am Geriatr Soc. 2015; 63: 142-150Crossref PubMed Scopus (269) Google Scholar, 27Smith D. Andrzejowski J. Smith A. Certainty and uncertainty: NICE guidance on 'depth of anaesthesia' monitoring.Anaesthesia. 2013; 68: 1000-1005Crossref PubMed Scopus (23) Google Scholar, 28Aldecoa C. Bettelli G. Bilotta F. et al.European Society of Anaesthesiology evidence-based and consensus-based guideline on postoperative delirium.Eur J Anaesthesiol. 2017; 34: 192-214Crossref PubMed Scopus (488) Google Scholar including the white paper by Mahanna-Gabrielli and colleagues.1Mahanna-Gabrielli E. Schenning K.J. Eriksson L.I. et al.State of the clinical science of perioperative brain health: report from the American society of Anesthesiologists brain health initiative Summit 2018.Br J Anaesth. 2019; 123: 464-478Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar However, the anaesthetic dosing and BIS parameters reported raise serious concerns about feasibility and, potentially, safety. CODA's secondary finding is not simply that a 0.36 MAC reduction in anaesthetic administration results in lower postoperative delirium rates; it implies that low concentrations of hypnotic agents, during major surgery, may be required to achieve this outcome. Whilst it remains an area of clinical equipoise whether delirium (i) is preventable by decreasing anaesthetic administration, and (ii) whether brief postoperative delirium causes long-term adverse effects, such as accelerated cognitive decline and dementia, there is no equipoise surrounding our responsibility as anaesthetists to ensure intraoperative hypnosis with general anaesthesia, except in truly extenuating clinical circumstances. Brain health is undoubtedly a major perioperative concern. However, small or even large reductions in anaesthetic administration, guided by the EEG and its spectrogram,1Mahanna-Gabrielli E. Schenning K.J. Eriksson L.I. et al.State of the clinical science of perioperative brain health: report from the American society of Anesthesiologists brain health initiative Summit 2018.Br J Anaesth. 2019; 123: 464-478Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar are unlikely to have a major salutary impact on postoperative delirium and other neurocognitive disorders; the clinical relevance of preclinical data suggesting the potential for anaesthetic neurotoxicity in adult humans is itself questionable.29Bilotta F. Evered L.A. Gruenbaum S.E. Neurotoxicity of anesthetic drugs: an update.Curr Opin Anaesthesiol. 2017; 30: 452-457Crossref PubMed Scopus (38) Google Scholar We ourselves are strong proponents of incorporating the EEG into anaesthetic practice, but it is important to acknowledge that the most reliable evidence to support our practice applies to limited scenarios, such as the prevention of awareness in the setting of total i.v. anaesthesia with neuromuscular block.30Avidan M.S. Mashour G.A. Prevention of intraoperative awareness with explicit recall: making sense of the evidence.Anesthesiology. 2013; 118: 449-456Crossref PubMed Scopus (70) Google Scholar
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