We thank Drs. Scarlett, Hahn, Jacobsohn, and Avidan for their interest in our article and for their thoughtful comments.
They express concern that the Bispectral Index (BIS) may not be a reliable indicator of “anesthetic depth,” as two of the components of the latter, analgesic adequacy and hemodynamic state, have not been shown to be reflected in the BIS index. However, numerous peer-reviewed studies demonstrate that BIS is a reliable metric of hypnotic depth, the component of the anesthetic state relating to memory, recall, and awareness (1–3). Our study reports on this component, and we agree that interpretation of our results should be limited to this facet of the anesthetic state. An inherent limitation of many studies in the anesthesia literature is the confounding presence of surgical stimulation, the effects of which cannot be easily separated from those of the anesthetic. The Glass et al. study (2) is cited because it is probably the most complete evaluation of the relationships among BIS, sedation state, consciousness, recall, and agent concentrations without the confounding influence of surgical stimulation. There are, however, many other studies that have found the same utility of BIS to quantify the hypnotic state in surgical settings (3,4). Nevertheless, we recognize that in practice, anesthesia and surgery are inevitably linked, which is why we stated in our paper “Because anesthetic drugs and dosing, hypnotic depth, surgical stimulation and hemodynamic variables are strongly interacting elements, carefully controlled prospective studies will be required.”
Drs Scarlett, Hahn, Jacobsohn, and Avidan correctly point out that other BIS values may be chosen to define cumulative deep hypnotic time. We chose the value of 45 because it is the lower end of the target BIS titration range in the treatment group of the Food and Drug Administration-required study that demonstrated the efficacy of the BIS monitor (5). There certainly may be other threshold BIS values that are more appropriate. Ideally, these would be evaluated by comparing the outcomes of large numbers of patients randomized to specific, tightly-controlled BIS values (e.g., 50, 45, 40, 35). We are unaware of any such studies, however.
Scarlett et al. propose a reasonable alternative method of quantifying cumulative deep hypnotic time as an area under the curve. We are reporting an observation, however, and believe that a definitive judgment regarding the best metric of cumulative deep hypnotic time will not be possible without greater insight into the mechanism of this association and the results of randomized trials to assess the issue of causation. Further post hoc reanalysis would not shed further insight on the basic finding of the study.
The absence of consistent hemodynamic agent data is a clear limitation of our study. As we lack complete data on adjuvant use, we excluded data on the administration of β adrenergic-blockers in response to reviewers’ comments. Interestingly, we found the use of β adrenergic blockers intraoperatively to be associated with an increased risk of long-term mortality, possibly reflecting their use as rescue agents in hemodynamically unstable patients. This association did not affect the findings regarding BIS.
We recognize that we do not understand the mechanism of our findings but view our study as hypothesis-generating and hope that it serves as the basis for future investigations of possible mechanisms. The correspondents seem to believe that anesthesia-induced alterations in the inflammatory cascade could not plausibly influence cancer mortality 1 yr later. However, there are numerous studies linking anesthesia, surgery, inflammatory processes, and levels of inflammatory markers to cancer outcomes (6–8). Moreover, the literature on the role of the central nervous system in cytokine pathways is also increasing rapidly. We would simply point out that these various considerations are not mutually exclusive. By referring to the possible role of increased cerebral susceptibility to the effects of anesthetics, we were attempting to raise the possibility that the brains of some patients, whether for genetic reasons or by virtue of their illness, may have an altered response to anesthesia with implications for their general health.
Finally, the important issue of conflict of interest was discussed in our response to a previous Letter to the Editor. Moreover, we had the data analyzed by an independent statistician at Duke University Medical Center before the submission of the manuscript and the results of this second analysis were in agreement with the findings reported in the study.
Terri G. Monk, MD, MS
B. Craig Weldon, MD
Department of Anesthesiology
Duke University Medical Center
Vikas Saini, MD
The Cardiovascular Specialists LLC
Jeffrey C. Sigl, PhD
Aspect Medical Systems
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