Relationship between bispectral index values and volatile anesthetic concentrations during the maintenance phase of anesthesia in the B-Unaware trial

Abstract

Background: Hypnotic depth during anesthesia affects electroencephalography waveforms and electroencephalogram-derived indices, such as the bispectral index (BIS). Titrating anesthetic administration against the BIS assumes reliable relationships between BIS values, electroencephalogram waveforms, and effect site concentration, beyond loss of responsiveness. Associations among BIS, end-tidal anesthetic concentrations (ETAC), and patient characteristics were examined during anesthetic maintenance, using B-Unaware trial data.

Methods: Pharmacokinetically stable ETAC epochs during intraoperative anesthetic maintenance were analyzed. A generalized estimating equation determined independent relationships among BIS, ETAC (in age-adjusted minimum alveolar concentration equivalents), patient characteristics, and 1-yr mortality. Further individual and population characteristics were explored graphically.

Results: A total of 3,347,523 data points from 1,100 patients were analyzed over an ETAC range from 0.42 to 1.51 age-adjusted minimum alveolar concentration. A generalized estimating equation yielded a best predictive equation: BIS = 62.9-1.6 (if age younger than 60 yr) -1.6 (if female) -2.5 (if American Society of Anesthesiologists physical status more than 3) -2.6 (if deceased at 1 yr) -2.5 (if N2O was not used) -1.4 (if midazolam dose more than 2 mg) -1.3 (if opioid dose more than 50 morphine equivalents) -15.4 × age-adjusted minimum alveolar concentration. Although a population relationship between ETAC and BIS was apparent, interindividual variability in the strength and reliability of this relationship was large. Decreases in BIS with increasing ETAC were not reliably observed. Individual-patient linear regression yielded a median slope of -8 BIS/1 age-adjusted minimum alveolar concentration (interquartile range -30, 0) and a median correlation coefficient of -0.16 (interquartile range -0.031, -0.50).

Conclusions: Independent of pharmacokinetic confounding, BIS frequently correlates poorly with ETAC, is often insensitive to clinically significant changes in ETAC, and is vulnerable to interindividual variability. BIS is therefore incapable of finely guiding volatile anesthetic titration during anesthetic maintenance.

Figures

Figure 1

Characteristics of a depth-of-anesthesia (DOA) monitor capable of finely titrating anesthetic dose during maintenance. 1A, the monitor would have a high correlation coefficient between the DOA index and the effect-site (e.g., brain) anesthetic concentration within a single patient (blue line). Considerable within-patient variability at a single effect-site concentration is undesirable (red line). 1B, the monitor would be sufficiently sensitive to reflect changes in relative effect-site concentration within a single patient (blue line). An index that is insensitive to clinically significant changes in relative effect-site concentration (red line) would be uninformative. 1C, the monitor would display a predictable index value at which emergence from anesthesia occurs across a population of patients (1C; blue lines). If the emergence DOA index value differs among patients (1C; red lines), anesthetic emergence is unpredictable and the index cannot be used for safely titrating anesthesia while reducing the incidence of intraoperative awareness. Note that among-patient differences in anesthetic sensitivity (i.e. modest right- or left-shift, or modest differences in slope) are acceptable (blue lines); among-patient differences in DOA emergence threshold are not (red lines).

Figure 2

“Residual plot from a linear mixed effect model for bispectral index (BIS) data, with a normal curve superimposed, demonstrating that the residuals are not normally distributed with substantial excess kurtosis”

Figure 3

A contour plot (A) and a three-dimensional bivariate joint probability distribution function (B) from 3,347,523 pharmacokinetically censored data points from 1,100 patients over an end tidal anesthetic concentration (ETAC) range from 0.42 to 1.51 age adjusted minimum alveolar concentration (aaMAC) during anesthetic maintenance. The median was 1,883 data points from individual patients (range, 1 to 26,140). These plots demonstrate that for a given aaMAC concentration, the response variable (i.e., bispectral index (BIS) value) displays its highest densities in the low forties. The mode density of BIS values remains in the low forties over the ETAC range from 0.42 to 1.51 aaMAC (>98% of the ETAC data).

Figure 4

Box and whisker plots of bispectral index (BIS) ranges at six age-adjusted minimum alveolar concentration (aaMAC) ranges: th and 97.5th percentiles.

Figure 5

Density plots of bispectral index (BIS) values for 0.8

Figure 6

Single-patient bispectral index (BIS) and end tidal anesthetic concentration (ETAC) in age-adjusted minimum alveolar concentration (aaMAC) equivalents over time (6A1,6B1, 6C1) and BIS-aaMAC relationship (6A2,6B2,6C2). Patients were selected from those whose pharmacokinetically-censored data was over a >0.5 aaMAC range on the basis of their BIS-aaMAC slope in context of population characteristics. Patient A (6A1 & 6A2), −31 BIS units per 1 aaMAC increase (25th percentile for slope). Patient B (6B1 & 6B2), −9 BIS units per 1 aaMAC increase (median slope). Patient 6C (6C1 & 6C2), −0.3 BIS units per 1 aaMAC increase (75th percentile for slope).