It is widely believed that the effects of general anesthesia are temporary and that they disappear as the drugs are cleared from the body. There is, however, strong evidence from animal experiments to suggest that standard doses of routine anesthetics may produce long-lasting learning and memory impairments that persist for weeks or months after anesthetic exposure.1–4 This is associated with τ-hyperphosphorylation,5–7 caspase-3 activation,8–11 and β-amyloid deposition in the brain.9,12–14 Each of these processes is directly linked to the development of Alzheimer disease. Although human studies remain inconclusive,15 the current data suggest that the anesthetic per se may be an important contributor to adverse cognitive outcome after surgery.16–18
Intraoperative monitoring of processed electroencephalogram (EEG), such as the bispectral index (BIS), has been shown to facilitate titration of anesthetic drug delivery.19,20 The BIS monitor incorporates time-domain, frequency-domain, and bispectral analysis of raw EEG signals. This is displayed as a dimensionless number, ranges from 0 (isoelectric EEG) to 100 (fully awake), to indicate the depth of anesthesia.19 By aiming at a BIS value between 40 and 60 during anesthesia, the doses of hypnotic agents were reduced by 11% to 27%.20,21 This is associated with improved early recovery profiles and faster emergence from anesthesia.22,23 However, it is unclear whether lower doses of anesthetics with BIS monitoring will decrease the risk of postoperative cognitive dysfunction (POCD). We therefore conducted a randomized controlled trial, known as the Cognitive Dysfunction after Anesthesia (CODA) Trial (Centre for Clinical Trials number, CUHK_CCT00141) to determine whether BIS-guided anesthesia decreases the incidence of POCD and postoperative delirium in elderly patients undergoing major surgery.
Patients were enrolled between January 2007 and December 2009. We recruited patients who were 60 years or older, scheduled for elective major surgery, which was expected to last for 2 hours or longer, with an anticipated hospital stay of at least 4 days. Patients were excluded if they were not expected to be available for, or cooperate with, postoperative interviews. Patients with illiteracy, language difficulties, or significant hearing or visual impairment were also excluded. Other exclusion criteria included patients with major psychosis who were taking tranquillizers or antidepressants, patients with diseases of the central nervous system, suspected dementia or memory impairment with a score on the mini-mental state examination (MMSE) of 23 or less.24
As patient performance in neuropsychology assessment generally improves with repeated test administration, we recruited another 221 nonsurgical patients from the specialist medical clinics to quantify this learning effect. These patients underwent identical neuropsychological measurements during the study period. They fulfilled the above inclusion and exclusion criteria except they were not planned to undergo surgical procedure within 6 months of enrollment.
Study Design, Randomization, and Blinding
The CODA Trial was a prospective, randomized, double-blinded, and parallel group study. After enrollment and immediately before induction of anesthesia, the attending anesthesiologist randomized the patient according to a computer-generated random group assigment, accessed through an intranet system. Patients were allocated to receive either BIS-guided or routine care anesthesia. Patients, surgeons, and all research staff, including those responsible for postoperative data collection and outcome assessment, were blinded to the treatment identity. The Clinical Research Ethics Committee approved the study protocol, and all patients gave written informed consents.
Patients were assessed within 1 week before the scheduled surgery. Details of medical comorbidity, surgical history, and the number of years of education received were recorded. Surgery, perioperative care, and safety monitoring were provided according to usual local guidelines.
In the operating room, a BIS Quatro sensor (Covidien, Mansfield, MA) was applied to the forehead of each patient, before the induction of anesthesia according to the manufacturer’s recommendations. This was connected to an A-2000 System XP monitor that was concealed from the patients and surgeons. In the BIS group, anesthetic dosage was adjusted to achieve a BIS value between 40 and 60 from the commencement of anesthesia to the end of surgery. An audible alarm was set when the BIS number fell out of the prescribed range. In patients allocated to receive routine care, anesthetic drug administration was titrated according to clinical judgment. This was generally to maintain arterial pressure within 15 mm Hg of the baseline and the heart rate within the 40 to 90 beats/min range. If there were signs of inadequate anesthesia, such as sweating, flushing, movement, or swallowing, anesthetic dose was increased. BIS monitoring was continued in the routine care group, but the BIS number, its trend, and the EEG waveform were omitted from the display, specifically designed for this trial. BIS values, hemodynamic, and other expired gas data were recorded in 5-second intervals using a data acquisition program. We calculated the time-averaged BIS value during the maintenance of anesthesia. The amount of time when BIS was <40 was recorded as an indicator of deep anesthesia.
In both groups of patients, cessation of general anesthesia was timed so as to facilitate early awakening after wound closure. We recorded the recovery times from the end of anesthesia to eye opening and discharge from the postanesthesia care unit (PACU) when the modified Aldrete score was 9 or more.25 For patients who were transferred to the intensive care unit (ICU) for postoperative mechanical ventilation, we recorded the time to tracheal extubation as a marker of early recovery.
After surgery, patients were regularly reviewed by the research staff until hospital discharge. We assessed delirium daily in the mornings after surgery using the confusion assessment method criteria.26 Delirium was defined as acute fluctuating course of inattention and either disorganized thinking or an altered level of consciousness. Patients who were alert were asked to rate their quality of recovery (QoR) using the Chinese QoR score.27 Before operation and 3 months after surgery, patients completed a short-form health survey (SF-36) to indicate the quality of their functional health status.
We measured cognitive function within a week before surgery, and again at 1 week and 3 months after surgery. All assessments were conducted by trained research staff in a quiet room.
Patients were asked to complete a Chinese version of the cognitive failure questionnaire (CFQ) to indicate potential subjective problems with perception, memory, and motor function.28 A battery of 3 neuropyschological tests was then administered to all patients.
- Verbal fluency test requires patients to name as many words as possible from a predefined category (eg, animals) within 60 seconds. We recorded the number of words that are correctly recalled from the relevant category.29
- Chinese auditory verbal learning test is a word-list learning task that assesses verbal learning, retention, and recognition memory.29 We recorded the total number of recalled words (out of 15) from over 5 learning trials and those recalled 30 minutes later.
- Color trial making tests the psychomotor speed, and we recorded the time taken to connect the number and color sequences.30
The tests were chosen because they were sensitive to deficits in verbal memory, language, attention, psychomotor skills, and executive functions and have been validated for local population.29,30 To minimize learning effects, we used parallel forms of each test and the sequence of test administration was randomly assigned.
Change in objective cognitive function was measured by comparing the baseline performance of neuropsychology tests with test results obtained at 1 week and 3 months after surgery. We calculated a Z score to indicate the standardized change in each of the neuropsychology tests by subtracting the average learning effect measured in the nonsurgical controls and divided by the SD in this cohort. A large Z score indicates deterioration in a particular cognitive measure from the baseline compared with the nonsurgical controls. We defined POCD if 2 or more Z scores were 1.96 or greater.31,32 Similarly, subjective cognitive dysfunction was defined by calculating a Z score for the CFQ using the same approach.
We defined the primary outcome, as POCD at 3 months after surgery. Secondary outcomes were POCD at 1 week, delirium in hospital, and the rate and QoR after anesthesia and surgery. We also recorded major postoperative complications up to 3 months after surgery. Cardiac complications included myocardial infarction (defined as typical rise and fall in cardiac troponins, associated with either ischemic symptoms, changes in electrocardiography, echocardiography, coronary angiography, or pathologic findings), heart failure, and thromboembolism (detected by venography, duplex ultrasonography, ventilation-perfusion scan, or spiral computerized tomography). Respiratory complications included pneumonia (defined as pulmonary infiltrates in radiologic studies, associated with fever, leukocytosis, or positive culture in sputum or blood sample) and desaturation (oxygen saturation <90% for >5 min). Infective complications included wound infection (defined as purulent discharge with or without positive microbial culture) or any new infection requiring antibiotic therapy.
Assuming the incidence of POCD in the routine care group was 30%,33 we determined that a sample size of 450 patients per group would provide 90% power to detect an absolute risk reduction of 15% (2-sided α=0.05).
All patients undergoing surgery with general anesthesia and randomized to BIS monitoring or routine care were considered as comprising the intention-to-treat population for all primary and secondary analyses. POCD as the principal outcome was compared between groups using the Fisher exact test. Recovery times were calculated as median time to event with interquartile ranges (IQR) using Kaplan-Meier survival analysis and were compared between groups by log-rank test and the Cox proportional hazards model for possible covariate adjustment, with assessment of the requisite proportionality assumptions. Other secondary endpoints were analyzed using the Fisher exact test or χ2 tests. Continuous variables were compared between groups using unpaired t test. Risk factors contributing to POCD and postoperative delirium were analyzed using logistic regression. Only factors that scored a P value <0.20 in the univariate analysis were incorporated in the final multivariable model. All reported P values are 2 sided.
We approached 1657 elderly patients scheduled for major surgery. After screening, 62 patients were excluded because the preoperative MMSE was ≤23 points: 10 patients refused consents, 4 patients rejected the study for no specific reason, other patients were excluded because of their participation in other studies. A total of 921 patients were included in the CODA Trial, of whom 462 patients (50.2%) received BIS-guided anesthesia and 459 patients (49.8%) were randomized to the routine care group. A total of 85.0% and 90.7% of patients completed the 1-week and 3-month assessments, respectively (Fig. 1). Baseline characteristics and surgical details of the trial participants and were similar between study groups (Table 1).
Details on anesthetic administration are shown in Table 2. BIS monitoring reduced end-tidal volatile concentration by 29.7% [95% confidence intervals (CI), 25.9-32.8, P<0.001] and estimated propofol effect site concentration by 20.7% (95% CI, 12.1-31.9, P<0.001). Consequently, the average BIS value during surgery in the BIS-guided anesthesia was higher than that in the routine care group. The amount of time when BIS<40 was also lower in the BIS-monitored patients.
Primary and Secondary Outcomes
The test scores of CFQs and their performance in neuropsychology testing at baseline, 1 week, and 3 months after surgery are summarized in Table 3. There were fewer patients with delirium in the BIS group compared with routine care during the index hospital admission, with absolute risk reduction 8.6% (95% CI, 3.4-13.7), but the rates of POCD at 1 week after surgery were not different between groups. In contrast, BIS-guided anesthesia reduced the rates of POCD up to 3 months after surgery (Table 4). The absolute risk reduction was 4.5% (95% CI, 0.25-8.9). The number needed to treat was 23 (95% CI, 6-391). The benefit of BIS monitoring was unaffected with a multivariable analysis that adjusted for age, sex, education status, average BIS value during anesthesia, and postoperative delirium while in hospital (adjusted odds ratio 0.67; 95% CI, 0.32-0.98; P=0.025).
Table 5 summarizes the recovery times and postoperative complications after BIS-guided or routine care anesthesia. BIS monitoring shortened recovery times in PACU. The mean differences in eye opening from cessation of anesthesia was 4.3 (95% CI, 2.7-5.8) minutes, with hazard ratio 1.53 (95% CI, 1.32-1.79), and that for PACU discharge, the mean difference was 12.5 (95% CI, 7.0-18) minutes, with hazard ratio 1.40 (95% CI, 1.20-1.63).
For patients transferred to the ICU for postoperative ventilation, BIS monitoring had no effect on time to tracheal extubation or ICU discharge, and the hazard ratios (95% CI) were 1.29 (0.92-1.69) and 1.23 (0.94-1.62), respectively. The median length of hospital stay was 7 days (IQR, 5 to 10 d) in the BIS-guided group and 8 days (IQR, 6 to 12 d) in the routine care group, P=0.98. Cardiac and respiratory complications did not differ between groups, but the rate of postoperative infection was significantly higher in the routine care group. The QoR score during hospital stay and the physical summary measure of SF-36 scale at 6 months after surgery were reported better after BIS-guided anesthesia compared with routine care.
Risk Factors of POCD and Delirium
Independent predictors of POCD and postoperative delirium are listed in Table 6 and Table 7, respectively. A total of 179 patients were found to have delirium during initial hospitalization and 104 patients had POCD at 3 months after surgery. Among these factors, large doses of anesthetic, a low average BIS value during surgery, long period of deep anesthesia (BIS<40), and increasing age remained significant in a multivariable analysis. We were unable to demonstrate a relationship between postoperative infection and POCD, but our analysis is probably underpowered to detect the modest correlation.
Patients with delirium during hospitalization were more likely to perform poorly in the neuropsychology tests during the first week and 3 months after surgery, odds ratio (95% CI): 16.7 (8.7-32.1) and 12.3 (7.5-20.0), respectively.
Our study demonstrated that in elderly patients undergoing major surgery, there was 21% decrease in the propofol delivery and 30% decrease in the administration of volatile anesthetic when BIS was maintained between 40 and 60 during surgery. BIS-guided anesthesia also reduced the risk of postoperative delirium during initial hospitalization by 35% and POCD at 3 months after surgery by 31%. Patients receiving BIS monitoring recovered from anesthesia more quickly than routine care, with earlier eye opening and faster discharge from PACU. BIS-guided anesthesia also significantly decreased the risk of postoperative infection, but our multivariable analysis could not demonstrate a measurable relationship between the occurrence of infection and POCD.
Our Study in Relation to Previous Data
Two randomized trials have evaluated the effect of anesthetic depth on POCD. In contrast to our findings, Farag et al34 reported better cognitive function with higher processing index in 74 patients receiving larger doses of anesthetics (BIS, 30 to 40) after noncardiac surgery. Similarly, An et al35 reported a lower incidence of POCD in 80 patients undergoing craniotomy for microvascular decompression when BIS was maintained in the range of 30 to 40 (deeper anesthesia) compared with those in the lighter anesthesia group (BIS, 55 to 65). However, both studies focused on cognitive measurements in the early postoperative period. Given that cognitive assessments during this period are greatly influenced by postoperative pain, analgesic therapy, and physical disability, it is unclear that how these results might reflect the impact of anesthesia on POCD. Interestingly, in an observational study of 65 elderly patients having noncardiac surgery, anesthetic depth, measured by the median (5% to 95% percentiles) cerebral state EEG index, was similar in patients with POCD at 1 week after surgery [40 (32 to 55); n=9] compared with those who did not [43 (30 to 70); n=56], P=0.41.36 In this regard, the consensus statement on the assessment of neurobehavioral outcomes after cardiac surgery recommended that cognitive assessment should be performed at least 6 weeks after surgery to indicate nonsurgical insults to the brain.32 In the CODA Trial, we did not observe difference in cognitive performance between groups until 3 months after surgery. Nevertheless, it has been postulated that deep anesthesia, by reducing cerebral metabolism and stress response to surgery, may decrease POCD. In animal experiments, mice receiving a higher concentration of isoflurane demonstrated better performance in behavioral tests,37,38 but deep anesthesia with large doses of propofol has been associated with higher incidence of neurological deficits after cardiac surgery.39
Two large cohort studies have suggested potential harmful effects of deep anesthesia. Monk et al40 studied the outcome in 1046 patients after noncardiac surgery. Deep anesthesia, defined as cumulative time when BIS<45, significantly predicted 12-month mortality, with relative risk 1.24 (95% CI, 1.06-1.44; P=0.012). Similarly, Lindholm et al41 found an association between deep anesthesia, using the same definition, and 2-year mortality in 4087 patients having noncardiac surgery with intraoperative BIS monitoring, but this was only significant when preexisting malignancy was included, with hazard ratio 1.18 (95% CI, 1.08-1.29; P=0.003). Although these findings were intriguing, the 2 studies have been criticized for the observational cohort design and potential bias.42
The B-Aware Trial has recently reported a higher mortality with deep anesthesia, defined as BIS<40 for >5 minutes, during a median follow-up of 4.1 (range, 0 to 6.5) years after surgery, with hazard ratio 1.42 (95% CI, 1.04-1.93; P=0.03).43 Episodes of deep anesthesia were also associated with an increased risk of myocardial infarction and stroke during the follow-up, with hazard ratio 1.94 (95% CI, 1.12-3.35; P=0.02) and 3.23 (95% CI, 1.29-8.07; P=0.01), respectively. Although the B-Aware Trial was a large randomized study, the observations could not be considered as conclusive, because BIS data were obtained in only half of the patients (BIS-guided group) and that only intermittent BIS values were recorded. Furthermore, some of the important predictors for postoperative morbidity and mortality, such as cancer status, have not been included in the analysis.43,44 Interestingly, in a post hoc analysis of another large randomized study, the B-Unaware Trial, cumulative time with BIS<45 was predictive of mortality after cardiac surgery, with hazard ratio 1.29 (95% CI, 1.12-1.49),45 but not with noncardiac procedures, with hazard ratio 1.03 (95% CI, 0.93-1.14).46
More recently, 2 retrospective analyses of large anesthetic databases have suggested that a low BIS value in combination of low arterial pressure during low anesthetic delivery (triple low) was associated with 2.5- to 4-fold increase in mortality.47,48 This scenario suggested an increased sensitivity to anesthetic and may be a marker of underlying organ dysfunction and hypoperfusion. In this setting, a modest dose of anesthetic could result in relative drug overdose and may lead to poor outcome. The large body of evidence therefore suggested that deep anesthesia (absolute or relative) may contribute to adverse postoperative outcomes; however, a randomized controlled trial comparing 2 distinct levels of anesthetic depth will be required to establish the causal relationship. In the CODA Trial, we did not randomize patients to 2 levels of anesthetic depths, but we were successful to achieve a separation in BIS values and anesthetic dosage between groups. Given that patients in the routine care group, who received larger doses of anesthetics with lower BIS values, had poorer cognitive outcome, our data demonstrated that careful titration of anesthetics to avoid deep anesthesia produced long-term benefit in preventing POCD. The effect of deep anesthesia on other rarer postoperative complications, such as death, will require further studies. In collaboration with the Australian and New Zealand College of Anaesthetists Trials Group, we have started recruiting patients for the Balanced Anesthesia Trial (Australian New Zealand Clinical Trials Registry No: ACTRN12612000632897) to determine the impact of light versus deep general anesthesia on all-cause mortality at one year postoperatively, in 6500 moderate to high risk patients having major noncardiac surgery.
We found a substantial reduction in anesthetic exposure with BIS monitoring compared with routine care anesthesia. Our data are consistent with previous studies and meta-analyses.20,21,23 However, recent large effectiveness trials, the B-Unaware Trial and the subsequent BAG-RECALL Trial,49,50 showed no change in the anesthetic administration with BIS-guided anesthesia. It should be noted that both trials included an active comparator group, where anesthesia was titrated to maintain an age-adjusted minimum alveolar concentration (MAC)≥0.7. It is plausible that anesthesiologists may provide extraordinary vigilance to prevent unintentional awareness with the lowest possible anesthetic delivery in the comparator group. The specific study design could diminish the difference in anesthetic exposure between groups. Interestingly, in the B-Aware Trial, using routine anesthetic care as the control group, BIS monitoring reduced the estimated plasma concentration of propofol by 17% and dose of midazolam used by 20%.44
There are limitations with BIS monitoring during clinical anesthesia. A number of environmental and physiological factors may affect BIS performance. Electrical 50 Hz mains interference, electrocardiographic, electromyographic, and electrocautery artifacts introduce high-frequency signals and are the major source of errors.51,52 Unless these factors are carefully corrected, serious misinterpretation can occur.51 Nevertheless, despite the interindividual variability, BIS monitoring seems to provide useful information to track the anesthetic drug effect.51
Postoperative Delirium and POCD
We found that postoperative delirium was common (20%) after major surgery in the elderly and this is consistent with previous studies.53,54 More importantly, we noted that the risk factors for postoperative delirium were similar to those predicting POCD. This finding would suggest that the 2 adverse outcomes may have derived from a common mechanism, such as deep anesthesia. In this regard, our study showed that by limiting anesthetic exposure, there was a significant decrease in postoperative delirium and POCD. This should facilitate short-term rehabilitation and long-term functional recovery.
Strengths and Weakness of Our Study
Although we designed the study according to the published guidelines,31,32 the test scores of our neuropsychology battery cannot be directly compared with other studies, because different tests were used. Unfortunately, universal neuropsychology tests are currently unavailable. Nonetheless, we chose tests that are sensitive and culturally adoptable for the local population. We also included nonsurgical controls to adjust for the practice effect of repeated testing. Given that the incidence of postoperative delirium and POCD are comparable with other studies,31–33 we believe our methods are robust in detecting adverse cognitive events.
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. This is particularly important for the younger patients who appear to have less risk of developing POCD,55 and so, deep anesthesia may be less critical compared with the elderly.
The CODA Trial indicated that for every 1000 patients undergoing major surgery, BIS-guided anesthesia prevented 83 patients from suffering delirium during hospital admission and 23 patients from POCD at 3 months after surgery. Given that intraoperative low BIS value, long period of deep anesthesia (BIS<40), and large doses of anesthetic were predictors of POCD, BIS monitoring with careful titration of anesthetics should prevent unintentional deep anesthesia and may be useful for improving postoperative cognitive performance in the elderly.
Our study demonstrated that in elderly patients undergoing major surgery, titrating anesthetic to maintain a BIS value between 40 and 60 during surgery avoided episodes of deep anesthesia. This was associated with a reduction in the risk of developing delirium during initial hospitalization and POCD at 3 months after surgery. BIS monitoring also expedite recovery from anesthesia.
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The CODA Trial Group:
Prince of Wales Hospital, The Chinese University of Hong Kong: Matthew T.V. Chan, Tony Gin, Emily G.Y. Koo, Qinzhou Wang, Keung-Tat Lee.
Tuen Mun Hospital: Benny C.P. Cheng, Yau-Leung Ho, Chung-Wai Lau.
Neuropsychology Team: Tatia M.C. Lee, Zoe Y.S. Sun, Ming-wai Tsang, Candy K.W. Lok, Angel T.Y. Ip, Angela Mou, Matthew W.Y. Tsang, Joy M.T. Yip.