“The recognition of the existence of a problem is the first step in its solution.

”—Martin H. Fischer

IN 2005, a study by Monk et al .1was the first to suggest that cumulative deep hypnotic time (cumulative duration of low bispectral index [BIS]) was an independent predictor of 1-yr mortality after major noncardiac surgery. Not surprisingly, the “validity of the mortality–hypnosis finding” was questioned, necessitating further investigation.2The report by Kertai et al .3in this issue of Anesthesiology adds to the growing body of evidence confirming the association between cumulative duration of low BIS and postoperative mortality. In this investigation, 17.8% of patients died in the first 3 yr after cardiac surgery, with the risk of death increasing by 29% for every cumulative hour for which the BIS was less than 45 during surgery. Other perioperative factors associated with increased mortality included the EuroSCORE, erythrocyte transfusion, intraoperative infusion of norepinephrine, and prolonged intensive care unit stay.

As in the current study, previously published reports confirming the mortality–hypnosis association were all derived from secondary analyses of data collected prospectively for other purposes.3–6Lindholm et al .4examined the BIS data from a study originally designed to evaluate the effect of BIS monitoring on the incidence of intraoperative awareness and found that cumulative time at BIS less than 45 was associated with an increased risk of death for up to 2 yr after surgery. However, when preexisting malignancy was included in the analysis, the association between low BIS and mortality was found only in patients with malignancies associated with poorer life expectancies. The investigators in the B-Aware Trial recently reported their secondary analysis of long-term mortality and found that the absence of low BIS values (BIS < 40) was associated with improved survival and reduced morbidity (myocardial infarction and stroke).5Finally, a post hoc  analysis of an observational study originally designed to investigate the use of BIS to monitor consciousness in mechanically ventilated, sedated adult intensive care unit patients confirmed this association in a nonsurgical population.6The authors compared two groups of patients with similar demographic and severity of illness characteristics and found that 39% experienced burst suppression. Patients who experienced burst suppression had a significantly higher 6-month mortality rate compared with patients who did not have burst suppression when sedated (59 vs . 33%). These three studies along with the current report by Kertai et al .3indicate that the mortality–hypnosis association is valid and deserves further rigorous investigation.

All the previous publications investigating the effect of low BIS on postoperative outcomes have identified preoperative comorbidity as an important independent risk factor for postoperative mortality,1,4,5leading to the hypothesis that these high-risk patients may have an increased susceptibility to anesthetic effects.1Kertai et al.  3also found that increased preoperative comorbidity as defined by the EuroSCORE, a measure of cardiac operative risk, was associated with increased postoperative mortality. In this study, most patients (83%) with the longest duration of BIS less than 45 (> 4 h) had abnormal left ventricular ejection fractions. Similarly, 67% of these patients were on β-receptor blockers before surgery, suggesting a history of chronic hypertension. Hypertension and a history of heart disease are two of the most important factors associated with the presence of cerebral white matter lesions and brain atrophy.7,8Therefore, we can hypothesize that high-risk patients have increased brain sensitivity to anesthetic agents, resulting in lower intraoperative BIS levels when given the same anesthetic dose as for healthier patients. The clinicians in the study by Kertai et al.  administered similar amounts of inhalation anesthesia and adjuvant agents to patients during maintenance anesthesia (table 2),3suggesting that the BIS levels were not used for anesthetic management. The authors concluded that this finding indicates that the association of low BIS and mortality was independent of total anesthetic dose. However, another interpretation of these data can be posited. Expired anesthetic concentration is only an indirect measure of brain concentration and, by extension, cerebral anesthetic effect. There is evidence that brain impairment influences BIS readings. A study evaluating the performance of BIS in healthy and intellectually disabled children found that BIS levels were lower in the awake state, during anesthesia, and on the return of consciousness in intellectually disabled children.9If the patients with low BIS readings in the study by Kertai et al.  had more central nervous system compromise related to white matter lesions and/or brain atrophy, the low intraoperative BIS readings may have been an indication of excessive anesthetic administration, possibly contributing to worsened outcomes. As an analogy, consider the drug adjustments that are required in patients with hepatic or renal impairment. Obviously, this question cannot be definitively answered until techniques to monitor the cerebral concentrations of anesthetic agents are developed.

Although the mortality–hypnosis association remains poorly understood, the use of BIS-derived data to predict outcome after hypoxic-ischemic encephalopathy is logical and well established. Electroencephalographic testing has long been a part of the evaluation of patients in coma, and recent studies have shown that BIS can be helpful in predicting mortality and neurologic outcome in comatose patients with hypoxic-ischemic encephalopathy with normal body temperature10and those undergoing therapeutic hypothermia.11,12A study involving comatose patients with hypoxic-ischemic encephalopathy undergoing emergency surgery demonstrated that BIS data collected during surgery were a better predictor than physicians' clinical judgment or patients' pupillary light responses in identifying patients with a good chance of recovery.13Perhaps, low BIS during anesthesia will prove to be helpful in predicting other outcomes as well.

A central question remains unanswered regarding the mortality–hypnosis association: can anesthetic management influence long-term outcomes or is the BIS® monitor (Aspect Medical Systems, Newton, MA) simply identifying patients whose brains are especially sensitive to anesthesia? Stated another way, by avoiding deep anesthesia, as documented with BIS, can we improve outcomes or are low BIS levels just another marker of comorbidity associated with a greater risk of postoperative death? The secondary analysis of the B-Aware trial provides a glimpse into a possible solution to this question.5In the original study, patients at high risk for awareness were randomized to receive an anesthetic directed by routine clinical parameters (routine care) or by BIS values.14The target range of BIS in the BIS-directed group was 40–60. For the purposes of the secondary analysis, the investigators compared three BIS groups for postoperative morbidity (myocardial infarction and stroke) and mortality outcomes. The three groups were as follows: (1) patients randomly assigned to the routine care group (no BIS); (2) patients randomly assigned to the BIS-directed group who experienced BIS values less than 40 for more than 5 min (low BIS); and (3) patients who were randomly assigned to the BIS-directed group who did not experience a BIS less than 40 for more than 5 min (optimal BIS). The initial analysis found no difference in outcomes between the patients who had routine care and those who received BIS-directed care. However, on further investigation, the researchers found that the optimal BIS group had significantly lower mortality and morbidity rates compared with both the no BIS and the low BIS groups. These results suggest that although BIS monitoring per se  did not affect important outcomes, the maintenance of BIS values between 40 and 60 reduced the risk of morbidity and mortality.

The recognition of this problem raises multiple questions. Is low BIS just a marker of comorbidity and imminent death or will intraoperative BIS optimization improve outcomes in high-risk patients? Do high-risk patients have greater susceptibility to anesthetic agents than heathier patients? Is it even possible to maintain BIS at optimal levels in high-risk patients undergoing surgery? Will low intraoperative BIS values identify patients whose outcomes can be improved by intensive postoperative strategies? We now recognize that the hypnosis-mortality association exists; it is time to take the next step toward a better understanding of this phenomenon.

Terri G. Monk, M.D., M.S.,*B. Craig Weldon, M.D.†

*Department of Anesthesiology, Duke University Medical Center, Durham Veterans Affairs Medical Center, Durham, North Carolina. terri.monk@duke.edu. †Departments of Anesthesiology and Pediatrics, Duke University Medical Center.

Monk TG, Saini V, Weldon BC, Sigl JC: Anesthetic management and one-year mortality after noncardiac surgery. Anesth Analg 2005; 100:4–10
Drummond JC, Patel PM: Editorial board reproached for publication of bis-mortality correlation. Anesth Analg 2005; 101:1238–9
Kertai MD, Pal N, Palanca BJA, Lin N, Searleman SA, Zhang L, Burnside BA, Finkel KJ, Avidan MS; on behalf of the B-Unaware Study Group: Association of perioperative risk factors and cumulative duration of low bispectral index with intermediate-term mortality after cardiac surgery in the B-Unaware trial. Anesthesiology 2010; 112:1116–27
on behalf of the B-Unaware Study Group
Lindholm ML, Träff S, Granath F, Greenwald SD, Ekbom A, Lennmarken C, Sandin RH: Mortality within 2 years after surgery in relation to low intraoperative bispectral index values and preexisting malignant disease. Anesth Analg 2009; 108:508–12
Leslie K, Myles PS, Forbes A, Chan MT: The effect of bispectral index monitoring on long-term survival in the B-aware trial. Anesth Analg 2010; 110:816–22
Watson PL, Shintani AK, Tyson R, Pandharipande PP, Pun BT, Ely W: Presence of electroencephalogram burst suppression in sedated, critically ill patients is associated with increased mortality. Crit Care Med 2008; 36:3171–7
Pantoni L, Garcia JH: The significance of cerebral white matter abnormalities 100 years after Binswanger's report. A review. Stroke 1995; 26:1293–301
Appelman AP, Exalto LG, van der Graaf Y, Biessels GJ, Mali WP, Geerlings MI: White matter lesions and brain atrophy: More than shared risk factors? A systematic review. Cerebrovasc Dis 2009; 28:227–42
Valkenburg AJ, de Leeuw TG, Tibboel D, Weber F: Lower bispectral index values in children who are intellectually disabled. Anesth Analg 2009; 109:1428–33
Fábregas N, Gambús PL, Valero R, Carrero EJ, Salvador L, Zavala E, Ferrer E: Can bispectral index monitoring predict recovery of consciousness in patients with severe brain injury? Anesthesiology 2004; 101:43–51
Stammet P, Werer C, Mertens L, Lorang C, Hemmer M: Bispectral index (BIS) helps predicting bad neurological outcome in comatose survivors after cardiac arrest and induced therapeutic hypothermia. Resuscitation 2009; 80:437–42
Seder DB, Fraser GL, Robbins T, Libby L, Riker RR: The bispectral index and suppression ratio are very early predictors of neurological outcome during therapeutic hypothermia after cardiac arrest. Intensive Care Med 2010; 36:281–8
Myles PS, Daly D, Silvers A, Cairo S: Prediction of neurological outcome using bispectral monitoring in patients with severe ischemic-hypoxic brain injury during emergency surgery. Anesthesiology 2009; 110:1106–15
Myles PS, Leslie K, McNeil J, Forbes A, Chan M: Bispectral index monitoring to prevent awareness during anaesthesia: The B-aware randomized controlled trial. Lancet 2004; 363:1757–63