The current practice of general anesthesia emphasizes giving doses of anesthetic drugs that ensure that all patients are unconscious throughout surgery or other interventional procedures. Additional sedative and analgesic drugs are often given to prevent or to treat hemodynamic instability and in response to changing surgical stimulation. This approach is effective and safe for most of our patients.
However, delivering a dose of anesthetic that ensures unconsciousness for all patients means that those who are sensitive to anesthetics receive significantly more drug than necessary. Reducing the dose toward the threshold for consciousness becomes a matter of judgment, unless monitors that process the frontal lobe electroencephalograph (EEG) or evoked potentials to track anesthetic depth are used. These monitors make it possible to titrate anesthetic dose more precisely according to individual patient requirements. Marketing of these monitors, such as the bispectral index (BIS) monitor (Covidien Inc., Dublin, Ireland), has emphasized their use to ensure that the anesthetic doses administered are sufficient to prevent awareness. Their use to reduce unnecessarily deep anesthesia is more controversial.1–6
The Association Between Anesthetic Depth and Mortality
An association between relatively deep anesthesia and increased postoperative mortality has been demonstrated in 6 of 8 published observational studies (Table 1).7–15 These studies have been performed in a variety of patient populations with respect to the types of surgery, age, and comorbidities, and using a variety of methodologies and definitions of deep anesthesia. Six studies have shown a similar increase in relative risk of mortality of approximately 20% per year of follow-up. Elderly and comorbid patients undergoing major surgery are at most risk.
Editorial comments have emphasized that the association is not necessarily causal and may be an epiphenomenon whereby a low-processed EEG index value and sensitivity to anesthetic drugs are markers of significant comorbidity or frailty and increased risk of early death.1–6 This viewpoint is particularly supported by one study in which deep anesthesia was only associated with mortality when accompanied by relatively low anesthetic requirements, relatively low arterial blood pressures, or both (a “triple low”).12 This study included a large number of patients and used a fully covariate adjusted analysis. A more recent study that purported to use the same methodology failed to replicate these associations. It should be noted that the latter study used a different threshold for minimal alveolar concentration, included emergency cases in the analysis, and had a number of different criteria for the covariates.13 The former study also pointed to the possibility that differences in arterial blood pressure could have been a confounding factor in some of the published observational studies, a conclusion supported by a recent study using burst suppression for more than 5 minutes as a definition of deep anesthesia, where the combination of burst suppression and a low mean arterial blood pressure (MAP; <55 mm Hg) was strongly prognostic of poor outcomes.14 The conflicting results and methodologies have failed to end the controversy concerning the importance of overly deep anesthesia on anesthetic outcome.6 The risk is also not recognized by traditional risk stratification.15
In the intensive care setting, 2 small studies have shown a similar relationship between deep sedation and adverse outcomes including mortality.16,17 In this setting, an association has also been made between sedative levels that cause EEG burst suppression and poor outcome. Burst suppression is a common occurrence at BIS < 35, so these findings are also of relevance in the anesthetic setting.18,19
Risks of General Anesthetic Drugs
Several recent reviews have enumerated the adverse effects of general anesthetic drugs on the brain, but their long-term relevance to patient outcome is unknown.20,21 In small-animal models, anesthesia can invoke an inflammatory response, increase deposition of Alzheimer proteins, induce neuronal apoptosis, and cause prolonged postoperative cognitive dysfunction.20–25 These effects are associated with both volatile and IV anesthetic drugs.21,24 Morphine can induce tissue angiogenesis by a peripheral effect, and volatile drugs inhibit natural killer cell activity, increasing cancer metastasis.22,26 Other pharmacologic effects of anesthetic drugs include immune suppression and direct tissue toxicity.22,26
Human studies have confirmed relevant increases in Alzheimer disease biomarkers, phosphorylated τ, and amyloid β-42 in the early postoperative period.27–29 There also may be indirect physiologic effects because of cardiovascular or neuronal depression causing tissue hypoperfusion and hypoxia.30 Studies of cerebral oximetry have found an association between low cerebral oxygenation during anesthesia and both poor cognitive function and delayed hospital discharge.31–33 Loss of cerebral autoregulation accompanying general anesthesia and low MAP have also been associated with poor postoperative outcomes.34 Similarly, human studies have confirmed the suppression of the immune response and release of proinflammatory cytokines that occur with general anesthesia.35–39 Another possibility is that the opioid component of anesthesia and postoperative pain relief may promote cancer recurrence by a peripheral effect.40 The long-term relevance of these findings to patient outcome is unclear.
The association of deep anesthesia and poor postoperative outcome introduces the possibility that the adverse effects are dose related, and minimizing anesthetic dose will reduce the incidence of unfavorable outcomes. It is unknown whether these effects are physiologic in origin, resulting from impaired organ perfusion, immune or neuronal suppression, or a pharmacologic effect, as a result of toxicity of the anesthetic drugs, or whether the association is spurious.
We recently proposed a model to explain the complex interplay between the various perioperative factors that may lead to a poor outcome: relative anesthetic overdose, organ dysfunction, and organ hypoperfusion, each of which may lead to a low BIS value and result in an apparent association between low BIS values and death.41 We observed that the apparent association between low BIS values and death may have been due to anesthetic intolerance (a surrogate marker of high risk for death) rather than inherent anesthetic toxicity. The unanswered question is whether titrating to higher BIS values and decreasing anesthetic dosage, while maintaining adequate organ perfusion, will improve patient outcomes.
Small Clinical Trials
Three prospective studies of patients randomly assigned to specific levels of anesthetic depth have been published recently.42–44 A study of 921 ASA physical status I and II patients, aged ≥60 years, undergoing major surgery under general anesthesia, found that patients receiving routine care had lower BIS values compared with those randomly assigned to receive BIS-guided anesthesia (mean BIS, 36 vs 53).42 There was a 30% reduction in volatile anesthetic use in the BIS-guided group, lower rates of early postoperative delirium (16% vs 24%), less postoperative cognitive dysfunction at 3 months (10% vs 15%), and a 50% reduction in postoperative complications (11% vs 21%). A similar study comparing BIS-monitored general anesthesia with BIS concealed in 1155 patients did not report a difference in postoperative cognitive dysfunction; however, both groups had a mean BIS of 39.43 Nevertheless, there was a lower rate of postoperative delirium in the BIS-guided group. This finding was attributed to the lower incidence of EEG burst suppression in the BIS-guided group (indicating the avoidance of very deep anesthesia). Another prospective study of BIS-guided anesthesia was abandoned for futility after 381 patients had been randomly selected, in part, because of the inability to track BIS 55 or BIS 35 targets with sufficient accuracy to convincingly separate the 2 treatment groups.44 There were no differences in any outcomes, including 1-year mortality, although the statistical power for these comparisons was limited. The uncertainty over the impact of deep anesthesia evident in the current literature has motivated us to design and undertake the Balanced Anesthesia Study to assess the impact of anesthetic depth on patient outcome after major surgery.
The overall goal of the Balanced Anesthesia Study is to assess the impact of anesthetic depth on patient outcome after major surgery. The primary hypothesis is that “light” anesthesia, defined as a BIS target of 50, will reduce all-cause mortality in comparison with “deep” anesthesia, defined as a BIS target of 35, in patients aged ≥60 years presenting for major surgery under general anesthesia. The trial is an international multicenter, randomized, parallel-group, double-blind (patients and investigators), prospective, intention-to-treat, safety, and efficacy study.
Patient Selection and Sample Size
Patients aged ≥60 years, of ASA physical status III or IV, undergoing general anesthesia for surgery lasting >2 hours (defined as from anesthesia induction to finish of wound closure), and who are expected to have a postoperative stay of 2 or more days are included. One-year all-cause mortality in this group is expected to be approximately 10% based on Australasian studies of elderly patients and the Balanced Anesthesia pilot study.9,45,46 The relative reduction in mortality in the light anesthesia group is expected to be 20%, giving an absolute risk reduction from 10% to 8%. Power analysis using a = 0.049 and b = 0.2 indicates that 3250 patients are required in each group. The α-threshold is reduced to allow for a single interim analysis of mortality (see below). We estimate that recruiting 6500 patients will take 4 years, with 40 to 50 centers internationally. The study is being conducted in accordance with current International Conference on Harmonisation and Good Clinical Research Practice guidelines.
Trial Design Considerations
Other processed EEG depth monitors such as spectral entropy (GE Healthcare, Pittsburgh, PA) were considered for inclusion. However, all the observational studies of anesthetic depth have used BIS monitoring, and studies comparing spectral entropy with BIS have shown poor correlation between the 2 algorithms in some patients.47–49 A disadvantage of BIS monitoring is the very steep dose-response curve for volatile anesthetic drugs with a subsequent flat plateau to the dose-response curve over a wide range of clinically relevant concentrations in some patients.50 Although this effect causes some convergence in mean BIS between the groups, separation of BIS targets can still be achieved and wide separation of anesthetic dose has been shown in prospective studies.42,46
Choice of Treatment Groups
Comparison of a BIS-targeted group with a standard care group was considered. This approach has been problematic in the published prospective studies.42,43 The definition of standard of care is not obvious, with wide variation in depth targets noted among patient groups, anesthesiologists, and institutions. For many institutions, standard care includes the use of BIS, resulting in significant overlap between the 2 groups, as in the study by Radtke et al.43 We have chosen 2 different anesthetic depths, rather than a standard-of-care group for comparison, to reduce the confounding effect of patients in the standard-of-care group having anesthesia that is similar in depth to the treatment group.
The choice of BIS targets for light and deep anesthesia was based on previous studies where BIS was blinded and the manufacturer’s recommendations. The study by Chan et al.42 had a mean BIS of 36 (interquartile range, 31–49) in the routine care group. The study by Kertai et al.11 had a mean BIS of 43 and SD of 9. Therefore, we chose a BIS target of 35 for the “low” group, because these data suggest that this would be well within the bounds of usual practice for many patients receiving general anesthesia without BIS or where the anesthesiologist is blinded to the BIS values.42,43,51 We chose a BIS target of 50 for the “high” group. This is in the middle of the manufacturer’s recommended range for adequate hypnosis during general anesthesia and is associated with a low risk of awareness.51,52,a The studies by Chan et al.42 and Kertai et al.11 also support the choice of BIS 50 for the high group. Although 15 BIS units of separation between the 2 groups is not large, the BIS scale is not linear and the difference in anesthetic requirements between these 2 targets has been shown to be approximately 50%.42,46,b Therefore, the study targets are within the range of clinically acceptable practice, and so the study results will be generalizable to standard anesthetic care.
Anesthesia is maintained with predominantly volatile anesthetic drugs in the Balanced Anesthesia Study. BIS does not track drugs whose main action is at N-methyl-D-aspartate receptors well, accordingly we have excluded nitrous oxide from the study.53 Ketamine infusion up to 25 mg/h is permitted, but not bolus doses or higher infusion rates that would constitute a major part of the anesthesia and have also been shown to increase the BIS level during anesthesia.54,55
Maintenance of anesthesia with propofol infusion was excluded from the trial. Propofol maintenance was included in several of the positive prospective studies.8,9,11 However, inclusion of propofol maintenance is problematic, because the mechanism by which propofol produces the anesthetic state is different from that of volatile anesthesia. Propofol also has anti-inflammatory effects, and if propofol were to have a different outcome from volatile-based anesthesia, then the power of the study to detect a significant difference would be reduced.56
Choice of Primary Outcome
The primary end point is all-cause mortality at 1 year after surgery. Disability-free survival was considered for the primary outcome.57,58 The latter is probably a more relevant measure from a patient-centered perspective but is weakened as a primary end point by a lack of precedents in the anesthetic literature to guide an accurate power analysis. All-cause mortality was the primary outcome of most of the observational studies to date.
Secondary outcomes include major morbidities, hospital process data, long-term patient-centered disability, and pain measures to capture a broad range of plausible harms or benefits of deep or light anesthesia.
- Major postoperative morbidities are myocardial infarction (MI), cardiac arrest, pulmonary embolism (PE), stroke, sepsis, and surgical site infection (Table 2). The first 4 of these end points will also be grouped with mortality as a composite “major complications” end point. The definitions are the same as in other Australasian outcome studies in anesthesia.58–60
- Duration of intensive care unit stay
- Duration of hospital stay
- Awareness is actively searched for using the modified Brice awareness questionnaire administered on day 1 postoperatively or the first available time thereafter.61,62
- Quality of anesthesia recovery is assessed on the first 3 postoperative days using the quality of recovery 15-item score.63 This abbreviated version of the full 40-item questionnaire has similar accuracy to the full questionnaire.
- The World Health Organization Disability Assessment Schedule 2.0 12-item (WHODAS-12) score is used as a general assessment of patient-centered outcome.64 The score has several advantages in this setting. It has undergone extensive external validation in >65,000 patients globally, has been translated into multiple languages, and can be self- or interviewer-administered. It is administered preoperatively and at 1 month and 1 year postoperatively. The score has been shown to track postoperative disability in surgical patients.65,66 This will enable between-group comparisons and within-patient comparisons to be made and will provide valuable public health information about patient outcome after major surgery in the elderly.
- Persistent postoperative pain: Patients are actively questioned about persistent pain at 1 month and 1 year using the modified Brief Pain Inventory.67,68 If persistent pain is reported, the Neuropathic Pain Questionnaire is administered.68
- Cancer recurrence is actively searched for, as defined in Table 2.
An Endpoint Adjudication Committee, chaired by an internal medicine physician and including an intensive care physician and anesthesiologist as members, verifies and adjudicates the major morbidity study end points and resolves uncertainty relating to the defined outcomes in individual patients to ensure consistent coding of study outcomes. Most of these definitions and measures are in use in other major outcome studies in anesthesia to allow comparison of outcomes between studies.
Assessment for Eligibility
Patients scheduled for both elective and nonelective surgery are being recruited. All patients are given adequate time for explanation, reflection, and discussion before consenting to participate. Patients who are eligible but not recruited are recorded in a study recruitment log that includes the reason for not participating.
Randomization and Group Allocation
Before randomization, the attending anesthesiologist records a target range for the MAP that they intend to maintain during the case and whether neuraxial block will be a part of their anesthetic management. These a priori decisions are required to avoid confounding by decisions to allow lower MAP in patients in the deep anesthesia group compared with the light anesthesia group. An a priori decision regarding neuraxial block placement is required to achieve similar utilization of neuraxial block in both allocated groups and avoid further MAP confounding. Block randomization using blocks of 8 stratified by site is used in a 1:1 ratio through an online randomization service. Randomization is performed as close as practical to the time of anesthesia induction. The Balanced Anesthesia Study is an intention-to-treat trial, and any participant who is enrolled, randomly assigned to a treatment group, and has surgery (whether this is the intended surgery) will be included for the duration of the study. All patients and study personnel, except for the attending anesthesiologist, will remain blind to group allocation. The anesthesia record is concealed in a sealed envelope at the end of the case to maintain blinding of study personnel postoperatively.
Patient demographic details and medical history are recorded. A 12-lead electrocardiogram, blood hemoglobin, creatinine, and albumin are also measured. Other preoperative investigations are performed as per standard practice at the recruiting center. Baseline Charlson comorbidity score and WHODAS-12 score are recorded.69,70 The Charlson score will measure whether the 2 groups are equivalent according to disease severity at baseline. The WHODAS-12 will provide a baseline for subsequent measurements.
Intraoperative care will be according to standard practice at the recruiting center. All choices of sedative or hypnotic anesthetic drugs, analgesics, muscle relaxants, and the addition of regional or local anesthesia to the general anesthesia regimen are at the discretion of the attending anesthesiologist, except for the exclusion of nitrous oxide, propofol maintenance, and ketamine infusions >25 mg/h. Likewise, the decision to continue or discontinue perioperative medications is left to the attending anesthesiologist. Sedative premedication is allowed. Induction of anesthesia can be through IV or inhaled routes. The BIS is monitored continuously by the standard frontal sensor. Intraoperative monitoring conforms to the local standard of care, with heart rate, MAP, and end-tidal drug concentration recorded for analysis, electronically if possible, preferably at 1-minute intervals and at a maximum of 5-minute intervals. When invasive arterial blood pressure measurement is used, this will be recorded in preference to noninvasive arterial blood pressure measurement.
During the maintenance phase of anesthesia, the BIS value targeted is 35 or 50 according to the group allocation. Anesthesiologists must aim to keep the BIS value within 5 units of this target for 90% of the case. Similarly, the attending anesthesiologists aim to maintain MAP within the a priori specified range at least 90% of the time. The Balanced Anesthesia pilot study data and early randomized controlled study data suggest that there is a subgroup of patients who cannot be maintained at the allocated BIS target using acceptable doses of anesthetic drugs.46 This was most usually patients with BIS values >35 in the deep group and BIS values <50 in the light group. Protocol deviations may sometimes be necessary because patient safety considerations are paramount, and this is recorded on the case report form. Other relevant monitored variables and drugs administered are recorded.
Patients are followed up daily while in hospital. Analgesic and antiemetic requirements are noted, and patients are screened for predetermined outcomes, adverse events, and serious adverse events. Serious adverse events are reported to the data monitoring committee as per standard good clinical research practice. Blood tests, pathology, electrocardiogram, imaging studies, and other investigations are ordered as clinically indicated by attending physicians according to local institutional practice.
Assessment After Hospital Discharge
Postoperative interviews are conducted by telephone or in person at 1 month and 1 year after surgery. All patients are screened for mortality, other outcomes, and adverse events, and the WHODAS-12 score and pain questionnaires are administered.
At the 1-year follow-up, if the patient scores >4, less than their preoperative baseline WHODAS-12 score, then the date of onset of disability is determined. To be counted as an outcome in the study, a new disability must be present for at least 6 months. If the onset is >6 months before the interview, this is defined as new-onset disability. If the onset is <6 months from the interview, then a further interview is scheduled for the 6-month anniversary of onset of disability to determine whether the patient fulfills the criteria for definition of new-onset disability. Finally, a combination of postoperative interview, screening medical notes, and pathology reports is used to determine whether cancer recurrence has occurred.
Collection of Data
Data are collected by study personnel at the recruiting center and recorded on a written patient case report form. All data are then entered into an online database accessed through the study website (www.balancedstudy.org.nz). This is maintained by the University of Auckland (Auckland, New Zealand). A Data Quality Committee oversees the database and identifies missing data and inconsistencies to be corrected with local staff before being uploaded to a confirmed database. The Data Quality Committee is blinded to group allocation.
Monitoring for Bias and Adherence
BIS and MAP traces are scrutinized weekly for tracking to target and within range and are reported by center. The investigator undertaking this analysis is blind to patient identity but not to group allocation. These data are constantly monitored by the Data Quality Committee, and collated data are reported to the Operations Committee for review and back to the individual site coordinators for quality improvement.
All patients who are randomly selected and who have surgery as scheduled will be considered to be part of an intention-to-treat population for all primary, secondary, and safety analyses. Patients will be analyzed in the groups to which they were randomly assigned irrespective of BIS levels achieved. Baseline characteristics will be tabulated with summary statistics for the 2 groups.
The primary and secondary outcomes will initially be analyzed using the full analysis set population, i.e., using those individuals who have confirmed outcomes. The majority of participants will have assessments of the primary outcome and the 30-day secondary outcomes. Permission will be sought as necessary to extract these from national databases and local hospital records. Sensitivity analyses will also be performed, as appropriate, for which those with missing outcome data will be assigned a poor outcome. Complete listings, according to the randomized group, will be compiled of those lost to follow-up and include relevant explanations.
The presence of MI, cardiac arrest, stroke, PE, sepsis, surgical site infection, awareness, and persistent postoperative pain at 30 days and 1 year as appropriate will be compared between randomized groups using Mantel-Haenszel χ2 tests if the expected cell frequencies permit or Fisher exact test. The Mantel-Haenszel χ2 test enables stratification to be included in the analysis and is generally a more powerful test than Fisher exact test. In addition, a composite outcome comprising the presence of MI, cardiac arrest, stroke, PE, and death will be compared between randomized groups using a χ2 test. Relative risks and hazard ratios as appropriate with 95% confidence intervals will be calculated for these outcomes.
Additional analyses will also explore MI, cardiac arrest, stroke, PE, sepsis, surgical site infection, and cancer recurrence using Cox proportional hazards regression to develop a model of independent predictors of these outcomes. The randomized group will be added to this model to assist explanation of any observed differences in outcome between the randomized groups.
Secondary analyses will be performed on the per-protocol population, i.e., those who received the randomized treatment without protocol violation, and further analyses will explore the role of actual (rather than targeted) BIS levels on outcomes.
The adverse event rates for nonoutcome variables will be summarized for each randomized group as percentage of patients and as frequencies (number of occurrences) and compared between groups using χ2 test, Fisher exact test, and Poisson regression depending on incidence rates.
Additional analyses will explore the differential impact of randomized group depending on patient demographic and anesthetic variables by testing for the significance of the interaction of these subgroup variables and the randomized group and with the results displayed as forest plots. Demographic variables to be included in the analysis are age, sex, body mass index, ASA physical status, type of surgery, Charlson score, WHODAS-12 score, preoperative hemoglobin, creatinine, and albumin. The anesthetic variables included will be volatile anesthetic dose, MAP, regional block, inotropic support, inspired oxygen concentration, and estimated blood loss.
An interim analysis of the primary outcome for efficacy will be performed when 2000 participants have completed the 1-year follow-up. The P value for this analysis was set, using the O’Brien-Fleming procedure with rounding of the result, at P < 0.001, and the primary study analysis P value adjusted accordingly to 0.049, to preserve the type I error rate. The analysis will be performed on the intention-to-treat population with all randomly assigned participants included and analyzed according to the randomized treatment, irrespective of actual treatment. An interim analysis for futility will not be performed, because in this study demonstrating that there is no difference between the groups is equally important to demonstrating that there is a difference. Terminating the study early because it would not demonstrate a difference would not end the controversy because it would then not be adequately powered to support the conclusion.
Data Monitoring Committee
The study is overseen by an independent Data Monitoring Committee composed of 6 members appointed by the Health Research Council of New Zealand plus 2 expert anesthesiologist advisors. The primary responsibility of the committee is to safeguard the interests of patients who participate in the study. The committee monitors the conduct of the study and assesses its safety. Meetings are 6 monthly at which unblinded information on recruitment, eligibility violations, completeness of follow-up data, compliance with the protocol, and summaries of adverse events are presented. Findings are presented to the trial Steering Committee without unblinding the data.
Current Status of Trial
The study has been endorsed by the Australian and New Zealand College of Anaesthetists Clinical Trials Network. The study is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12612000632897). Currently, patients are being recruited in 40 centers in 5 countries, with another 5 centers in the process of seeking institutional approval to perform the study. As of September 2014, 1325 patients have been randomly selected. The Data Monitoring Committee has met twice and recommended that the study continue.
Study Organization and Funding
The trial organization is displayed in Figure 1. The trial coordinating and data management center is based in the Department of Anaesthesia and Perioperative Medicine, Auckland City Hospital, Auckland, New Zealand.
The Steering Committee is responsible for the governance of the study, including developing the protocol, establishing the trial offices, database and randomization service, oversight of recruitment and data consistency, data analysis, and promulgation of results. The Steering Committee appoints the trial Writing Committee, which will be responsible for the main study report.
Day-to-day running of the trial is overseen by the Operations Committee, which provides the written study resources, recruits and initiates trial sites, and supports the trial office with regard to data management and queries. The Endpoint Adjudication Committee oversees categorization of end points to maintain consistency among centers. They adjudicate end points and also randomly audit case report forms to judge end points for consistency. The Data Quality Committee reviews all the case report forms and computerized data records for completeness and reviews the BIS and MAP tracking to ensure sufficient accuracy.
Elderly and comorbid patients undergoing general anesthesia for major surgery are at high risk of postoperative morbidity and mortality.13,45 There is an increasing awareness that perioperative care may contribute to these adverse outcomes, but there are few large clinical trials evaluating the risks and benefits of specific anesthetic interventions. This study aims to answer the important question of whether anesthetic depth influences patient outcome. There is no consensus among anesthesiologists on this issue, and large variations in practice among institutions and individual anesthesiologists are evident.
The Balanced Anesthesia Study is a large randomized controlled trial to test the hypothesis that light anesthesia for major surgery in elderly, comorbid patients will reduce long-term morbidity and mortality when compared with deep anesthesia. The trial will have important ramifications for anesthesiologists and their patients irrespective of the results. If negative, it will provide reassurance that current practice is not causing our patients harm and may reduce costs associated with unnecessary EEG monitoring. If it shows that 1 treatment arm causes extra morbidity and mortality, then the results could be implemented immediately into medical practice and will improve patient care, reducing morbidity or mortality, and their associated health care costs. In addition, study end points have been aligned with other Australian and New Zealand College of Anaesthetists Clinical Trials Network studies to allow amalgamation of study databases as a resource for further investigation of anesthetic and surgical outcomes.
An association between low-processed EEG values and mortality has been identified in observational studies, but the clinical significance of the finding remains controversial. This randomized controlled trial aims to definitively answer the question of causality and whether titrating anesthetic depth makes a difference to patient outcome in a vulnerable patient group.
Name: Timothy G. Short, MBChB, MD, FANZCA.
Contribution: This author helped design the study, conduct the study, collect data, analyze data, and prepare the manuscript.
Attestation: Timothy G. Short reviewed the original study data and data analysis, attests to the data integrity and analysis as reported in the manuscript, and is the archival author.
Name: Kate Leslie, MBBS, MD, MEpi, FANZCA.
Contribution: This author helped design the study, conduct the study, collect data, and prepare the manuscript.
Attestation: Kate Leslie reviewed the analysis of the data and approved the final manuscript.
Name: Matthew T. V. Chan, MBBS, FANZCA.
Contribution: This author helped design the study, conduct the study, collect data, and prepare the manuscript.
Attestation: Matthew T. V. Chan reviewed the analysis of the data and approved the final manuscript.
Name: Douglas Campbell, BM, FRCA, FANZCA.
Contribution: This author helped design the study, conduct the study, collect data, analyze data, and prepare the manuscript.
Attestation: Douglas Campbell reviewed the original study data and data analysis and attests to the data integrity and analysis as reported in the manuscript.
Name: Christopher Frampton, BSc (Hons), PhD (Cant).
Contribution: This author helped design the study, analyze the data, and prepare the manuscript.
Attestation: Christopher Frampton reviewed the analysis of the data and approved the final manuscript.
Name: Paul Myles, MBBS, MPH, MD, FCARCSI, FANZCA, FRCA.
Contribution: This author helped design the study, conduct the study, collect data, analyze data, and prepare the manuscript.
Attestation: Paul Myles reviewed the original study data and data analysis and attests to the data integrity and analysis as reported in the manuscript.
This manuscript was handled by: Ken B. Johnson, MD.
a Brain Monitoring with BIS: A Clinical Overview (Covidien Inc., Colorado, USA).
b Short TG, van Schalkwyk J. Death by BIS: does deep anaesthesia matter? Abstract, Annual Auckland Anaesthetic Consultants Meeting Proceedings, August 2011.
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