Pick up the Pieces

I N this issue of ANESTHESIOLOGY, Kertai et al. 1 report on the association between anesthetic depth, as measured electroencephalographically with a bispectral index (BIS) monitor, and long-term mortality. It is the fifth observational study on a continuing controversy, which began in 2005 with a paper by Monk et al. We will try to pick up the pieces here. Nonrandomized studies have indicated potential advantages of administering anesthesia using processed electroencephalograms. These potential advantages include rapid emergence from anesthesia, decreased anesthetic requirements, less postoperative nausea and vomiting, and earlier discharge from the postanesthesia care unit. When the first randomized multicenter trial, the B-Aware Trial, allocated 2,463 patients at high risk of intraoperative awareness to BIS-guided anesthesia or routine care, they found an 80% reduction in awareness incidence, albeit with few endpoints (2 vs. 11 cases of definite awareness). In contrast, an American monocenter trial, the B-Unaware Trial, compared BIS monitoring with end-tidal gas monitoring in 2,000 patients at high risk for awareness and found two cases within each study arm. Without attempting to address why the anesthesia community has remained skeptical of brain-function monitoring, the most controversial question remains whether there is a possible causal, rather than purely statistical, association between deep anesthesia and long-term outcomes. In 2005, Monk et al. used multivariable time-to-event analysis to create a predictive model for 1-yr mortality in 1,046 patients undergoing noncardiac surgery. The overall mortality in that study was 5.5%, where cancer was the cause of 52% of these deaths. Independent predictors were comorbidity (included as dichotomized Charlson comorbidity index), cumulative “deep hypnotic time” (number of minutes BIS values were less than 45), and intraoperative hypotension. The paper by Monk et al. generated a storm of reactions, largely in response to the authors’ suggestion of causality: “These associations suggest that intraoperative anesthetic management may affect outcomes over longer time periods than previously appreciated.” Main criticisms included: confusing causation and statistical association; combining comorbidities to a single score and dichotomizing Charlson comorbidity score and BIS values, both resulting in information loss and risk of residual confounding; and coauthorship by an employee of Aspect Medical Systems, Newton, MA (manufacturer of BIS monitor), suggesting a possible conflict of interest. Other readers commented that the BIS value range of 40 – 45 that prevented awareness in trials was actually considered “deep anesthesia” in the study by Monk et al. The pathophysiologic link between deep anesthesia and mortality is still unknown. Monk et al. postulated that deep anesthesia might interfere with the immune response, resulting in organ damage by (as yet) undefined mechanisms, such as inflammation and hypercoagulation-induced disturbances of the microcirculation. Lindholm et al. subsequently reported an association between low intraoperative BIS values and 1-yr mortality in 4,087 noncardiac surgery patients. Without malignancy status as a covariable in the multivariable model, the relationship established was similar to that observed by Monk et al. However, with the addition of malignancy status, the relationship between low BIS and mortality disappeared. The authors concluded: