We found a 9.2% nonsignificant reduction in postoperative delirium in the BIS-guided group, with both a raw and adjusted odds ratio of approximately 0.6 (Table 2, Table 4). This is consistent with other published trials (Table 5)6–8 which, taken together, demonstrate an odds ratio of 0.56 for BIS-guided anesthesia (Fig. 2). Because of the exploratory nature of the meta-analysis presented here, this finding must be viewed as preliminary. However, it does lend support to the need for a large trial to confirm or refute the effectiveness of BIS guidance in preventing delirium.
There are several plausible mechanisms by which BIS guidance could decrease postoperative delirium. One hypothesis is that electroencephalogram (EEG) or BIS guidance leads to avoidance or minimization of periods of EEG burst suppression or persistent suppression. These EEG patterns are not seen during physiological sleep and have been associated with adverse outcomes in ICU patients.22 Results from the SuDoCo clinical trial (ISRCTN36437985) suggested that percentage of time with an intraoperative burst suppression ratio higher than zero was an independent risk factor for postoperative delirium with an estimated hazard ratio of 2.5 (95% CI, 1.23–4.91, P value =0.01).8 When BIS values are below 20 to 30, the EEG burst suppression ratio is inversely correlated with the BIS and is probably a major determinant of the BIS.23 In the current trial, however, the patients randomized to the ETAC group and the patients who were delirious in the ICU did not have an increased proportion of intraoperative time with BIS <20 (Tables 1 and 2). Future research should attempt to clarify how intraoperative EEG-based monitoring could decrease postoperative delirium.
Four independent predictors of postoperative delirium were identified in this study: number of units of pRBCs administered intraoperatively, ASA PS, EuroSCORE, and average ETAC. ASA PS is a subjective measure of preoperative comorbidities and patient condition, while EuroSCORE is an objective measure of comorbidities and surgical risk. EuroSCORE has been identified as a significant, independent predictor of delirium risk in a cardiac surgical population, though neither study considered ASA PS.24,25 While some features of the EuroSCORE had to be estimated in our population, composite metrics reduce the risk of a type 1 error compared with including individual characteristics. EuroSCORE is a significant predictor of other adverse outcomes in cardiac surgical patients, including prolonged ICU length of stay26 and mortality, both in a large multicenter population27 and in a population from our institution.28 While the association between ASA PS and postoperative delirium has been better studied in noncardiac surgical populations,29,30 it is not surprising that ASA PS is related to postoperative delirium in this cardiothoracic surgical population as well. Furthermore, red blood cell transfusion has also been identified as a risk factor for postoperative delirium in cardiac surgical patients25,31 and was confirmed to be associated with delirium risk in our population.
One of the most interesting findings of this analysis was the association between average ETAC and postoperative delirium. There are 3 potential explanations for this finding. First, the simple interpretation is that administering increased volatile anesthetic concentration results in protection against delirium. A second, and in our view more likely, explanation is that there may be an epiphenomenal association, whereby patients who are at risk for delirium are also treated differently intraoperatively by the anesthesia professional providing their care, as manifested by relatively lower concentrations of administered anesthetic. Our findings are consistent with a third explanation that vulnerable patients receive a relative overdose of anesthetic drug and develop delirium. Although the dose they receive is less than that of patients who do not develop delirium, given the underlying susceptibility, it is nonetheless a relative overdose. However, if a relative overdose in vulnerable surgical patients were to increase the risk of postoperative delirium, we would expect regional anesthesia to be associated with a lower incidence of postoperative delirium than general anesthesia. A meta-analysis of small trials that randomized surgical patients to regional or general anesthesia surprisingly found no change in risk for delirium with general anesthesia (odds ratio, 0.88; 95% CI, 0.51–1.51).32
Patients with a high EuroSCORE, who were ASA PS 4, and who received more intraoperative blood transfusions, were more likely to become delirious, suggesting that delirious patients were more vulnerable to cardiovascular instability. We hypothesize that frailty is reflected in both the cardiovascular system and the brain as reduced “cognitive reserve,” which has been advanced as an encompassing theme common to many nonmodifiable risk factors for postoperative delirium.33 Thus, cardiovascular sensitivity to anesthesia, a situation in which anesthesia professionals may therapeutically decrease volatile anesthetic delivery rates, may characterize patients at particular risk for postoperative delirium because of concomitant cognitive vulnerability. This second hypothesis is not mutually exclusive with the third, wherein vulnerable patients receive a relative overdose of anesthesia even at concentrations much lower than those without unusual vulnerability. Biochemically, the idea of precipitating factors (e.g., surgical inflammation, anesthetic drugs) acting on a vulnerable substrate has been explored by Maclullich et al.34 as “maladaptive sickness behavior,” where an insult to a vulnerable limbic-hypothalamic-pituitary axis induces an inappropriate or uncontrolled stress response, manifested as delirium. Thus, patients with maladaptive stress responses may be those who are less likely to receive high concentrations of volatile anesthetics because of concomitant cardiovascular frailty.
The major limitation of this study is its small sample size, rendering it vulnerable to imprecise findings and type II error. Also, no baseline formal assessment for preexisting delirium or other cognitive screening was performed; however, patients enrolling in the BAG-RECALL trial participated in an informed consent discussion before their surgery and were deemed able to consent. Recent studies comparing CAM-ICU diagnoses of delirium with those made with DSM-IV criteria,35 the nursing delirium screen (Nu-DeSc),36 and even unstructured bedside nursing evaluation37 have found lower sensitivity than previously reported, particularly in verbal patients; thus, this study may tend to underestimate delirium rates. Missing CAM-ICU assessments in our study population also may have resulted in an underestimate of delirium rates. Liberal inclusion of candidate predictors in statistical models is also subject to criticism;16 however, we attempted to mitigate that effect by pursuing a SSVS strategy, avoiding the use of iterative logistic regression and using composite metrics when possible. Although our variables of interest were selected a priori, this statistically permissive approach produces a model which should be taken as hypothesis generating only. This was also a single-center study conducted at a quaternary care center, and our findings might not be readily generalizable to a lower-acuity cardiothoracic surgical population.
In summary, we did not find that randomization to the BIS or ETAC-guided protocols decreased postoperative delirium in this patient population, but the results remain consistent with previous findings suggesting that BIS guidance decreases delirium after major surgery. There is therefore a need for a large randomized study to clarify whether or not EEG-guided anesthesia, with BIS or an alternative method, decreases postoperative delirium, specifically after cardiac or thoracic surgery. Furthermore, the mechanism by which EEG guidance could decrease delirium requires elucidation. The average ETAC during anesthetic maintenance, intraoperative units of pRBCs administered, EuroSCORE, and ASA PS are significant independent predictors of postoperative delirium in a cardiothoracic surgical population. Some of these factors may be modifiable, and they may be usefully incorporated into clinical screens to identify patients who are at increased risk of delirium after cardiac and thoracic surgery.
The authors thank David Kao who performed the meta-analysis. ELW thanks Jay Piccirillo, MD, FACS, for his support and guidance.
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