Deep Hypnosis as a Sign of “Imbalance” in Balanced Anesthesia

In this issue of Anesthesia & Analgesia, Leslie et al.1 show a potential role of intraoperative bispectral index (BIS, Aspect Medical Systems, Norwood, MA) monitoring in reducing long-term morbidity and mortality after surgery under general anesthesia. The report was a post hoc analysis of the B-Aware trial that was undertaken to determine whether intraoperative BIS monitoring reduced awareness during surgery. In this original trial, the authors found that BIS-guided titration of an anesthetic reduced intraoperative awareness by as much as 82%.2 To test the hypothesis that BIS monitoring improved survival, they reanalyzed the same data including the perioperative parameters, together with added follow-up data on the prognosis (death, myocardial infarction, and stroke) from 1947 patients. The authors found that BIS monitoring itself did not affect survival but that in patients with a BIS decrease <40 for >5 min there was an association with decreased survival (a hazard ratio for death of 1.42) and increased rates of myocardial infarction and stroke compared with those patients who did not show such a BIS decrease. The main findings of this study might suggest the use of BIS monitoring in controlling the depth of anesthesia within the appropriate hypnotic range, between 40 and 60, to improve prognosis of surgical patients. As the authors noted, survival and morbidity of surgical patients might be determined by systemic circulatory status and organ perfusion rather than anesthetic depth itself as indicated by the BIS value. Because of the nature of this retrospective analysis, intraoperative circulatory data were not available in sufficient detail to search for a possible correlation between low BIS values and hypotension. For the BIS-monitored cohort of patients, each anesthesiologist tried to titrate anesthesia depth to keep BIS values within the range of 40–60 and recorded an unintended or unavoidable incidence of BIS <40 for >5 min manually on the anesthesia record. Such notations helped the authors identify “oversedation” cases and test the hypothesis that BIS-guided titration might lead to reduced morbidity and mortality after surgery. Before the introduction of BIS and other types of brain function monitors to gauge anesthetic depth, it had been customary to titrate anesthetic agents by targeting an appropriate range of hemodynamic parameters, such as heart rate and systemic blood pressure. In the present era of “balanced anesthesia,” we have disassociated 3 components of anesthesia, i.e., unconsciousness, analgesia, and immobility, which are independently controlled with a hypnotic, an analgesic, and a neuromuscular blocking agent, respectively. An increase in heart rate and blood pressure sometimes signals awareness or insufficient analgesia, especially if combined with neuromuscular blockade. A decrease in heart rate and blood pressure, however, might indicate a relative overdose of a hypnotic or analgesic drug. Such a decrease in hemodynamic parameters beyond physiologically acceptable levels could potentially be associated with hypoperfusion of major vital organs. Changes in these parameters thus signal an “imbalance” in balanced anesthesia and prompt us to titrate each agent to recover normal circulation. What happens when a hypnotic is administered in an amount larger than that needed to just induce unconsciousness? Electrical and metabolic activities of the brain are reduced, with electroencephalographic changes leading to lower BIS values. We actually do not know the exact impact of anesthetic- induced hypotension on the function and viability of vital organs including the brain, the heart, the liver, and the kidney. We do know that each organ generally needs sufficient blood flow and perfusion pressure to maintain its normal function and that volatile or IV hypnotics might exert some protective effects in each organ by metabolic suppression and/or preconditioning.3 The vital organs might be tolerant against moderate hypoperfusion and/or hypoxia during anesthesia. Nevertheless, it is reasonable to assume that maintaining normal circulation and sufficient organ perfusion is the correct management to protect patients against the adverse outcomes of anesthesia. However, low BIS values are often observed during circulatory depression from causes other than anesthetic overdose, e.g., shock from excessive hemorrhage, heart failure, or peripheral vasodilatation, possibly from impaired cerebral neuronal activity secondary to reduced cerebral blood flow.4 Such critical conditions might well have led to a higher incidence of myocardial infarction or stroke. Indeed, the B-Aware trial involved high-risk patients undergoing cesarean delivery, high-risk cardiac surgery, acute trauma with hypovolemia, etc.2 Therefore, an incidence of BIS <40 for >5 min might have resulted primarily from circulatory depression rather than an absolute anesthetic overdose. Treating such relative anesthetic overdose by reducing anesthetic administration could cause intraoperative awareness; hence, strict anesthetic titration within the BIS range between 40 and 60 should play an important role in preventing awareness while treating hypotension. If the authors had shown possible correlations between the BIS values and the other intraoperative indices for circulation or organ perfusion, the present data would have been more informative in addressing the meaning of excessively low BIS values. Monitoring of BIS has become so common (at least in Japan) that the BIS number is now regarded as one of the perioperative vital signs, similar to heart rate and blood pressure. Although BIS is basically a simple index for the probability of awareness, with numbers ranging from 100 to 0,5 its detailed computation remains a “black box.” Raw electroencephalography is generally dominated by low-amplitude fast waves during awareness; high-amplitude, slow waves during unconsciousness or surgical anesthesia; and burst suppression or isoelectricity during deep anesthesia. The BIS value would be near 100 during awareness, between 40 and 60 during appropriate surgical anesthesia, and get closer to 0 with deepening of anesthesia. The computation of BIS incorporates several indices from spectral analysis of electroencephalographic activity and also clinical and behavioral data for the probability of awareness. Despite such arbitrary nature of BIS, this index apparently follows an almost linear trend from 100 to 0 as anesthesia deepens. Are the BIS values ranging between 40 and 60 optimal in terms of both anesthetic depth and their effects on organ perfusion? Accumulating evidence suggests that 95% of subjects are considered unconscious when BIS values are <50 when propofol or a volatile anesthetic drug is administered alone.6 Combined use of opioid drugs increases this threshold slightly, to approximately 60.7 A BIS value as low as 40 seems to indicate unconsciousness in nearly all subjects receiving general anesthesia.6 Despite such high reliability of BIS in predicting consciousness, prevention of intraoperative awareness by BIS monitoring has nevertheless remained controversial.2,8 Additionally, BIS values that are optimal for maintaining sufficient systemic circulation and organ perfusion have yet to be determined. There has been no evidence that BIS values of 35, for instance, might result in considerable circulatory depression compared with BIS values of 45; this will depend on many other factors, such as the systemic circulatory volume status, level of analgesia, extent of sympathetic blockade produced by neuraxial anesthesia, intensity of surgical stimulus, and the extent of stress-induced hormonal responses. Although the BIS value has been regarded as a “vital sign for consciousness,” this number seems too simple to evaluate systemic circulation or organ perfusion status on its own. However, low BIS values should be useful as one of the many premonitory signs of insufficient systemic circulation. Increasingly, more attention is being given to how anesthesia might affect long-term outcome after surgery.9 This study was stimulated by an earlier prospective study by Monk et al.10 on 1-yr mortality in which 1064 patients underwent major noncardiac surgery. The authors digitized deep hypnotic time, duration of BIS <45, from blindly recorded BIS trends, and showed that 1-yr mortality increased by 24.4% per hour of time that BIS was <45. Additionally, mortality was increased in patients with high comorbidities and low systolic blood pressure (<80 mm Hg).10 Another recent study by Lindholm et al.11 reexamined the impact of deep hypnotic time on 1- and 2-yr mortality of a similar cohort of 4087 patients. In this study, the authors also accounted for the patients' malignancy status, because cancer was the most common cause of death in the earlier study by Monk et al.10 Without malignancy status as a covariate, Lindholm et al. found a similar increase in the 1- and 2-yr mortality associated with deep hypnosis as to the earlier study by Monk et al.10 However, after stratification with malignancy status, they only found a statistical relationship between deep hypnosis and 2-yr mortality in patients with disseminated malignancy at the time of surgery. American Society of Anesthesiologists physical status, age, and malignancy status were by far the stronger predictors for mortality, consistent with earlier results.10 Deep anesthesia might also affect immunity and promote infection or tumor growth,12 which might increase morbidity and mortality, especially in patients with disseminated malignancy. Although the above earlier prospective studies agree that the largest contributing factors to remote mortality seem to be comorbidities at the time of surgery, age, and disseminated malignancy, the contribution of deep hypnotic time and low systolic blood pressure to remote mortality might be limited. Deep hypnosis and suppressed circulation could both result only secondarily to relative anesthetic overdose, depending on the context of surgery. Therefore, the impact of deep hypnosis on the prognosis of surgical patients must await a future randomized controlled trial that controls for other predictive factors such as comorbidity, malignancy, age, intraoperative circulatory status, and viability of major organs. Nonetheless, the information offered by the present retrospective survey motivates us toward a better anesthetic management using the strict titration of BIS to values between 40 and 60; it has added one piece of information to a line of evidence that suggests a potential role for BIS-guided anesthetic titration to improve the outcome of surgical patients. Let us look forward to the patients' healthy and happy smiles a year postoperatively and go for a safe drive with titrated, well balanced, and thoughtful anesthesia!