British Journal of Anaesthesia 113 (6): 897–9 (2014)Advance Access publication 29 May 2014 . doi:10.1093/bja/aeu147

EDITORIALS

‘Known unknowns and unknown unknowns’:electroencephalographic burst suppression and mortalityT. G. Short1* and K. Leslie2,3,4

1 Department of Anaesthesia and Perioperative Medicine, Auckland City Hospital, Auckland, New Zealand2 Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, Australia3 Anaesthesia, Perioperative Medicine and Pain Medicine Unit, Melbourne Medical School, and Department of Pharmacology,University of Melbourne, Melbourne, Australia4 Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia

* Corresponding author. E-mail: tims@adhb.govt.nz

There are known knowns; there are things we know that we know.There are known unknowns; that is to say, there are things thatwe now know we don’t know. But there are also unknownunknowns—there are things we do not know we don’t know.

Donald Rumsfeld 2002

The association between deep anaesthesia, as evidenced bylow processed EEG index values, and mortality has beenreported repeatedly,1 but the relationship between EEG burstsuppression and mortality has not been explored before in sur-gical patients. In this edition of the journal, Willingham and col-leagues use observational data from the B-Unaware andBAG-RECALL studies to investigate the relationship betweenburst suppression during general anaesthesia and mortalityin the next 90 days.2 – 4 They report that burst suppressionwas not associated with mortality [odds ratio 0.83 (95% confi-dence interval 0.55–1.25)]. Their study contrasts with the pre-vious work by Watson and colleagues5 who reported anassociation between burst suppression and 6 month mortalityin 125 mechanically ventilated patients [hazard ratio for deathwithin 6 months with burst suppression 2.0 (95% confidenceinterval 1.12–3.7, P¼0.02)].

The burst suppression pattern on the EEG occurs when cor-tical silence alternates with bursts of high-voltage activity.6

In the medical setting, burst suppression is often associatedwith brain metabolic failure resulting from a variety of patho-logical and traumatic conditions. Burst suppression may also

be intentionally induced; via hypothermia ordrug administrationbecause it is associated with a lower metabolic rate and maybe therapeutic, or unintentionally induced as a result of highanaesthetic drug administration. The anaesthetic drugs thatinduce burst suppression include benzodiazepines, propofol,and volatile agents and it occurs more commonly in elderlypatients.7 Burst suppression therefore may be a reflection ofharm, therapeutic, or unintentional depending on the setting.7 8

In animal models, drug-induced burst suppression has beenassociated with apoptosis in the developing brain and isthought to be a common mechanism for activation of apop-tosis caused by drugs with disparate mechanisms of action.9

Whether this occurs in humans, or is important to poor out-comes in elderly patients, is unknown. The burst suppressionpattern is easily recognized on the EEG and does not requirecomplex proprietaryalgorithms to be measured. The investiga-tion of whether burst suppression, as opposed to low processedEEG index values, is a harmful phenomenon in the general an-aesthetic setting is therefore important.

Both the study by Watson and colleagues and the currentstudy were post hoc analyses of data collected for anotherpurpose [bispectral index (BIS)-guided sedation in the criticallyill and BIS-guided anaesthesia to prevent awareness in surgicalpatients, respectively]. However, there were important differ-ences between the two studies that may explain their disparateresults, apart from the entirely different patient populations.

& The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.For Permissions, please email: journals.permissions@oup.com

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Watson and colleagues used Cox’s proportional hazard model-ling to account for important covariates such as age, priorhealth, and severity of illness. In contrast, Willingham and col-leagues added propensity score matching in order to overcomethe problem of the two patient groups not being equivalent atbaseline. This statistical technique finds control patients bymatching for patient characteristics that could be confoundingfactors (Willingham and colleagues used age, BMI, gender, race,ASA physical status, cardiac or non-cardiac surgery, and 19aspects of the past medical history—the ‘known knowns’).This technique is similar to that used by other authors whohave used observational data to explore the relationshipbetween low BIS values and mortality, including one of us.10 Itis important to understand the limitations of propensityscoring when interpreting the results of studies that use it.11

The current study is a good illustration of the issues.In these observational studies of anaesthetic depth, bias

may be present, because frail elderly patients are more likelyto record low BIS values or burst suppression and are alsomore likely to die after surgery than younger, fitter patients.The approach of matching ‘known knowns’ that may influenceoutcome using propensity score methods is intuitively obvious,but can lead to the erroneous impression that propensityscore-adjusted studies have a similar lack of bias to the goldstandard of a prospective, blinded, randomized controlledtrial, where, with a sufficiently large sample size, known butunmeasured covariates (‘known unknowns’) and unknown un-measured covariates (‘unknown unknowns’) are also balancedbetween the groups. Propensity scoring also performs betterwhen the numbers of events per covariate are low (,10) orthe numberof covariates is high andso it is a good choice ofstat-istical technique for the present study. Willingham and collea-gues met these criteria, although they were limited in theirselection of covariates by the original study designs (resultingin omission of at least one relevant ‘known unknown’—renaldisease)12 and of course, it is unlikely that ‘unknown unknowns’were balanced between the two groups.

The chosen outcome measurements and their timingcan also impact on results in post hoc analyses. The presentanalysis used a 90 day mortality outcome, although theB-Unaware and BAG-RECALL studies used different timeframes in the original and long-term follow-up studies andWatson and colleagues used 6 months. The studies ofdecreased survival from deep anaesthesia have variouslyreported mortality between 30 days and 4 yr.1 13 A short timeto assessment of mortality may reduce event rates and failto capture relevant long-term outcomes from anaesthesiaand surgery. A long period to assessment increases thechance of contamination of the signal from new unrelatedevents and increases the problem of missing data. In addition,although the authors collected continuous data on burst sup-pression in their patients, they chose a bivariate outcome of5 min of not necessarily contiguous burst suppression astheir independent variable. Watson and colleagues definedburst suppression as a suppression ratio .0 in any 63 s epoch.

Willingham and colleagues also reported an interactionbetween burst suppression, low arterial pressure, and

subsequent mortality. Again we do not know whether this iscausative because of the observational study design, but asthe result is similar to that found by Sessler and colleagues,13

it implies that a low BIS value may be a surrogate measurefor another factor, not necessarily directly related to anaes-thetic depth, such as frailty.

In the much richer cardiology literature, recent studies havecompared the accuracy of propensity score-matched observa-tional studies with randomized controlled trials of the sametreatment.14 15 Their conclusions include that propensityscore matching usually produced more extreme beneficialeffects than randomized controlled trials (13 of 17 instances),possibly due to publication bias, but that it did usually reflectthe outcome of subsequent randomized controlled studies(15 of 17 instances).14 It would be comforting to know thatthis also applies to the anaesthetic literature, but we doubtthere is sufficient outcomes research available to make sucha critical appraisal. Important to achieving reliability inpropensity scored studies when compared with randomizedcontrolled trials is knowing what the important covariatesare and prospectively making them ‘the known knowns’).

What conclusions should anaesthetists draw from anotherobservational study of anaesthetic depth and outcome? Pro-pensity score matching has certainly been used effectively toimprove the quality of the study. However, the result rests ona number of assumptions about the data and the choice of co-variates that were necessary to perform the analysis. Cliniciansare right to be inherently cautious in their interpretation of thecomplex statistical treatment and entailed result.16 Theauthors of the current study are also well aware of the limita-tions of their study. They correctly conclude that only a rando-mized controlled study can demonstrate or refute causality.

AcknowledgementThe authors are principal investigators of a large randomizedstudycomparing two levels of anaesthetic depth, The BalancedStudy: www.balancedstudy.org.nz.

Declaration of interestNone declared.

References1 Leslie K, Short TG. Low bispectral index values and death: the un-

resolved causality dilemma. Anesth Analg 2011; 113: 660–3

2 Willingham M, Ben Abdallah A, Gradwohl S, et al. Associationbetween intraoperative electroencephalographic suppression andpostoperative mortality. Br J Anaesth 2014; 113: 1001–8

3 Avidan MS, Zhang L, Burnside BA, et al. Anesthesia awareness andthe bispectral index. N Engl J Med 2008; 358: 1097–108

4 Avidan M, Jacobsohn E, Glick D, et al. Prevention of intraoperativeawareness in a high-risk surgical population. N Engl J Med 2011;365: 591–600

5 Watson PL, Shintani AK, Tyson R, Pandharipande PP, Pun BT, Ely EW.Presence of electroencephalogram burst suppression in sedatedcritically ill patients is associated with increased mortality. CritCare Med 2008; 36: 3171–77

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6 Ching S, Purdon PL, Vijayan S, Kopell NJ, Brown EN. Aneurophysiological-metabolic model for burst suppression. ProcNatl Acad Sci USA 2012;109: 3095–100

7 Besch G, Liu N, Samain E, et al. Occurrence of and risk factors forelectroencephalogram burst suppression during propofol–remifentanil anaesthesia. Br J Anaesth 2011; 107: 749–56

8 Niu B, Fang Y, Miao JM, et al. Minimal alveolar concentration of sevo-flurane for induction of isoelectric electroencephalogram inmiddle-aged adults. Br J Anaesth 2014; 112: 72–8

9 Mennerick S, Zorumski CF. Neural activity and survival in the devel-oping nervous system. Mol Neurobiol 2000; 22: 41–54

10 Leslie K, Myles PS, Andrew F, Chan MTV. The effect of BIS monitor-ing on long-term survival in the B-Aware trial . Anesth Analg2010; 110: 816–22

11 Okoli GN, Sanders RD, Myles P. Demystifying propensity scores(Editorial). Br J Anaesth 2014; 112: 13–5

12 Story DA, Fink M, Leslie K, et al. Perioperative mortality risk scoreusing pre- and post-operative risk factors in older patients.Anaesth Intensive Care 2009; 37: 392–8

13 Sessler DI, Sigl JC, Kelley SD, et al. Hospital stay and mortality areincreased in patients having a ‘triple low’ of low blood pressure,low bispectral index and low minimum alveolar concentration ofvolatile anaesthesia. Anesthesiology 2012; 116: 1195–203

14 Dahabreh IJ, Sheldrick RC, Paulus JK, et al. Do observational studiesusing propensity score methods agree with randomized trials?A systematic comparison of studies on acute coronary syndromes.Eur Heart J 2012; 33: 1893–909

15 Kuss O, Legler T, Borgermann J. Treatments effects from rando-mized trials and propensity score analyses were similar in similarpopulations in an example from cardiac surgery. J Clin Epidemiol2011; 64: 1076–84

16 Collins GS, Le Manach Y. Comparing treatment effects between pro-pensityscores and randomized controlled trials: improving conductand reporting. Eur Heart J 2012; 33: 1867–9

British Journal of Anaesthesia 113 (6): 899–902 (2014)Advance Access publication 16 July 2014 . doi:10.1093/bja/aeu221

Local anaesthetic use in cancer surgery and diseaserecurrence: role of voltage-gated sodium channels?S. P. Fraser1*, I. Foo2 and M. B. A. Djamgoz1

1 Neuroscience Solutions to Cancer Research Group, Division of Cell and Molecular Biology, South Kensington Campus,Imperial College London, London SW7 2AZ, UK2 Western General Hospital, Edinburgh EH4 2XU, UK

* Corresponding author. E-mail: s.p.fraser@imperial.ac.uk

Recurrence of canceraftersurgery remains a significant clinicalproblem. Interestingly, a number of retrospective studies havesuggested that application of local anaesthetics during cancersurgery can be beneficial to patients in a number of ways. First,local anaesthetic use can reduce the chance of subsequenttumour recurrence.1 – 3 Secondly, postoperative pain can besuppressed, thereby minimizing the need to use opioid analge-sics, which are known to be deleterious to the immunesystem.1 – 3 However, the mechanism(s) underlying theseeffects has not been clear. The discovery that cancer cellsand tissues express functional voltage-gated sodium channels(VGSCs), well known to be a target of local anaesthetics,provides an opportunity to re-evaluate these phenomena.

Voltage-gated ion channel expressionin cancerVGSCs are functionally expressed de novo both in vitro andin vivo in a variety of carcinomas, including breast, cervical,colon, lung (small-cell, non-small-cell, and mesothelioma),skin, ovarian, and prostate cancers.4 In vitro, VGSC activityhas been shown to enhance metastatic cell behaviours suchas lateral motility and invasion.5 6 Cancer cells also express a

range of other ion transporters, including voltage-gated potas-sium channels (VGPCs). The latter are commonly associatedwith apoptosis and growth.7 However, in relation to metastasis,VGPCs are thought to be down-regulated.5 8 ConcomitantVGSC up-regulation and VGPC down-regulation would enablecancer cells to become ‘electrically excitable’ and, in turn,‘hyperactive’ as the basis of their ‘aggressiveness’—this is theso-called ‘cellular excitability’ (‘CELEX’) hypothesis of meta-static progression.8

Beneficial effects of perioperative useof local anaesthetics on cancerand the possible role of VGSCsIt is well known clinically that breast cancer can reoccur aftersurgery (e.g. mastectomy), often within some 3 yr, and this isthought to be due to ‘showering’ of cancer cells duringsurgery and seeding in an immunosuppressed perioperativeenvironment.9 The use of local anaesthetic and paravertebralanalgesia were found to reduce cancer recurrence rates andimprove survival of breast cancer patients in comparisonwith those treated with general anaesthetic and morphine.10

In such applications, apart from the preservation of the

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