The blood concentration associated with loss of response (LOR) to command in 50% of subjects (CP50LOR) is an important measure of anesthetic potency. The CP50LOR of propofol alone is reported to be 2.32–4.4 μg/mL (1–8), depending on the age of the subjects and strength of the stimulus (i.e., verbal or tactile). Adjuvant hypnotic and analgesic drugs decrease propofol requirement for loss of the movement response after noxious stimulation (CP50) (3,9), but less is known about the effect of adjuvant drugs on LOR to command. Coadministered fentanyl decreases propofol CP50LOR (3,4), and mean propofol concentrations at LOR to command were 33% smaller in volunteers receiving propofol and 50% nitrous oxide (N2O) compared with propofol alone (10), but the effect of N2O on propofol CP50LOR has not been formally assessed. We therefore determined the CP50LOR in 40 healthy surgical patients receiving propofol alone or propofol with 67% N2O. In addition, we determined the bispectral index values (BIS; Aspect Medical Systems Inc. Newton, MA) associated with LOR to command in 50% of subjects (BIS50LOR) in the propofol-alone and propofol-N2O groups.
Methods
With approval from the Clinical Research Ethics Committee and written informed patient consent, 40 patients, aged 18–60 yr old and ASA physical status I–II, presenting for surgery under general anesthesia were studied. Exclusion criteria included conditions or medications known to affect anesthetic requirement, a risk of aspiration, body weight >150% of ideal, and an inability to communicate in English because of a language barrier, cognitive deficit, or intellectual disability. Using random number tables, patients were randomized to receive 100% oxygen (propofol-alone group) or 67% N2O in oxygen (propofol-N2O group). Randomization results were concealed in sealed opaque envelopes until patient consent was obtained.
No premedication was administered. An IV cannula was inserted into an antecubital vein and lactated Ringer’s solution 10 mL/kg, followed by an infusion at 10 mL·kg−1·h−1, was administered. Local anesthetic was injected subcutaneously over the radial artery in preparation for arterial blood sampling. Patients breathed spontaneously 100% oxygen or 67% N2O in oxygen, at a total gas flow rate of 6 L/min, via close-fitting facemask. A target-controlled infusion of propofol (Diprifusor®; AstraZeneca, Macclesfield, United Kingdom), using the Marsh et al. (11) pharmacokinetic data set, was then commenced at a target determined by the response of the previous patient in the same group (the Dixon up-and-down method) (12). The first patient in each group received a target blood concentration of 3 μg/mL, with subsequent patients receiving a target 0.5 μg/mL larger or smaller, depending on the response of the previous patient. After 15 min of infusion, the BIS value was recorded, and the patient was gently tapped on the shoulder and asked to open his or her eyes. The request was repeated three times at 5-s intervals. The response was assessed by an observer who was blind to the randomization and target propofol concentration. A positive response was recorded if the patient opened his or her eyes after any of the three requests to do so. The anesthetic was then allowed to proceed according to the needs of the patient, and surgery was commenced.
Arterial blood pressure was measured noninvasively every 5 min. Heart rate, hemoglobin oxygen saturation, inspired and expired gas concentrations, and the BIS were monitored continuously and recorded every 5 min. The BIS value just before assessment for response to command was recorded for use in the analyses.
Arterial blood samples were taken for propofol assay at 10 and 15 min of propofol infusion. The samples were stored at 4°C for up to 10 wk before analysis (propofol concentrations decrease at <0.2%/wk at 4°C). They were analyzed using a high-performance liquid chromatography assay modified from the method of Plummer (13). This assay is linear to at least 20 μg/mL, has a detection limit of 0.025 μg/mL, an interassay coefficient of variation of 4.1%, and an intraassay coefficient of variation of 4.9%.
Sample size was based on similar previous studies (1,7,10) and a guide of at least five patients per examined variable (14). Continuous data were tested for normality. Parametric data were summarized as mean ± sd, nonparametric data as median (range), and counts as number (%). Patient data at assessment for response to command were compared using unpaired two-tailed t-tests, Wilcoxon’s ranked sum test, χ2 tests, or Fisher’s exact tests, where appropriate. Logistic regression was used to determine CP50LOR and BIS50LOR values. Propofol concentration was log-transformed in this analysis. The effect of age was determined by including age as an independent variable in the logistic regression models. Confidence intervals for CP50LOR and BIS50LOR were derived using bootstrapping. Bootstrapping is a statistical method based on repeated random sampling with replacement from an original sample to provide a collection of new pseudo-replicate samples from which sampling variance (and therefore 95% confidence intervals [CI]) can be estimated. The relationship between BIS and measured propofol concentrations at 15 min, as well as target and measured concentrations, for each group were determined using generalized linear models. Propofol concentrations were log-transformed in this analysis. Analyses were performed using Stata 8.0 (Stata Corp., College Station, TX). A value of P < 0.05 was considered statistically significant.
Results
One patient in the propofol-N2O group became uncooperative; the study was abandoned before blood samples were obtained, and the data were excluded. Demographic characteristics were similar in the propofol-alone group (n = 20) and the propofol-N2O group (n = 19) in terms of age (38 ± 12 versus 40 ± 15 yr old), male sex (10 [50%] versus 8 [42%]), weight (76 ± 13 versus 72 ± 10 kg), and ASA physical status I and II, respectively (9 [45%] versus 10 [53%]). All patients breathed spontaneously, and no ventilatory assistance was required. At testing for response to command at 15 min, target and measured propofol concentrations were significantly larger, and BIS values were significantly smaller, in the propofol-alone group compared with the propofol-N2O group (Table 1).
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Table 1: At Assessment of Loss of Response to Command
The CP50LOR of propofol in the propofol-alone group was 4.58 μg/mL (95% CI, 1.14–15.36) and 2.67 μg/mL (95% CI, 2.28–3.17) in the propofol-N2O group (Fig. 1). The BIS50LOR was 60 (95% CI, 55–65) in the propofol-alone group and 75 (95% CI, 73–83) in the propofol-N2O group (Fig. 2). Age was not a significant predictor of response to command in this study in the propofol (P = 0.497) or BIS (P = 0.145) model.
Figure 1.:
Probability of loss of response (LOR) to command versus measured propofol concentration at 15 min. Raw data are displayed above, and 95% confidence intervals at 50% response are included. The relationship between measured propofol concentration at 15 min and responsiveness was defined by: log [p/(1 – p)] = a + b × [lnpropofol]. For the propofol-alone group, a = −3.14 (95% CI, −7.88–1.59; P = 0.19) and b = 2.10 (95% CI, −0.98–5.12; P = 0.18). For the propofol-N2O group, a = −7.23 (95% CI, −14 to −0.16; P = 0.045) and b = 7.36 (95% CI, 0.40–14.32; P = 0.038).
Figure 2.:
Probability of non-responsiveness to command versus bispectral index (BIS). Raw data for are displayed above and 95% confidence intervals at 50% response are included. The relationship between BIS and responsiveness was defined by: log [p/(1 – p)] = a + b*BIS. For the propofol-only group, a = 16.3 (95% CI: 1.07 → 31.5; P = 0.036) and b = −0.27 (95% CI: −0.53 → −0.01; P = 0.039). For the propofol-N2O group, a = 19.69 (95% CI: 0.17 → 39.20; P = 0.048) and b = −0.26 (95% CI: −0.50 → −0.007; P = 0.044).
In the propofol-alone group, the smallest measured propofol concentration (at 15 min) in a nonresponder was 2.89 μg/mL (target = 3.0 μg/mL; BIS = 57), and the largest measured propofol concentration in a responder was 6.04 μg/mL (target = 2.5 μg/mL; BIS = 81). In the propofol-N2O group, these values were 2.43 μg/mL (target = 2.0 μg/mL; BIS = 69) and 3.17 μg/mL (target = 2.0 μg/mL; BIS = 84), respectively.
Measured propofol concentration at 15 min (P = 0.0001) and N2O administration (P = 0.01), but not age (P = 0.58), were univariate predictors of BIS values. In a multivariate model, the apparent effect of N2O administration (P = 0.39) was shown to be caused by confounding measured propofol concentrations at 15 min (P = 0.007); that is, patients in the propofol-alone group had larger propofol concentrations and smaller BIS values than patients in the propofol-N2O group (propofol concentration was the true predictor of BIS not N2O administration) (Fig. 3).
Figure 3.:
Bispectral index (BIS) versus measured propofol concentration at 15 min. The relationship between BIS and measured propofol concentration at 15 min for all data was defined by: BIS = a + b × [lnpropofol], where a = 96.30 (95% CI, 82.39–110.21; P = 0.001) and b = −23.10 (95% CI, −33.38 to −12.76; P = 0.001). The coefficients for propofol-alone were: a = 75.88 (95% CI, 42.16–109.62; P = 0.0001) and b = −10.25 (95% CI, −31.93–11.43; P = 0.33). The coefficients for propofol-N2O were a = 103.27 (95% CI, 86.70–119.84; P = 0.0001) and b = −29.00 (95% CI, −44.20 to −13.80; P = 0.01). N2O (P = 0.39) was not a significant predictor of BIS values in a multivariate model.
Between 10 and 15 min of propofol infusion, measured propofol concentrations varied by –1% ± 13% (range, −25% to +29%). The median performance error of the target-controlled infusion device in the propofol-alone group was 23% (95% CI, 6%–61%) and 59% (95% CI, 34%–76%) in the propofol-N2O group. The median absolute performance error in the propofol-alone group was 26% (95% CI, 15%–61%) and 59% (95% CI, 34%–76%) in the propofol-N2O group. Target propofol concentration (P = 0.001) and N2O administration (P = 0.001) were significant univariate predictors of measured propofol concentration, but in a multivariate model, target concentration (P = 0.67) was no longer predictive because of an interaction with group allocation (N2O administration P = 0.01; interaction P = 0.01; target and measured propofol concentrations were larger in the propofol-alone group than the propofol-N2O group) (Fig. 4).
Figure 4.:
Target versus measured propofol concentration. The relationship between target and measured propofol was described by the equation: ln[measured propofol] = a + b × [target propofol], where a = 0.47 (95% CI, 0.13–0.80; P = 0.007) and b = 0.30 (95% CI, 0.18–0.42; P < 0.001). The dotted line represents unity.
Discussion
N2O (67%) decreased the CP50LOR of propofol by 43% in our study, confirming extensive clinical experience with propofol-N2O combinations for surgical anesthesia. This result is also consistent with values for LOR to command for isoflurane and sevoflurane in the presence of N2O (15,16) and the 33% decrease in mean venous propofol concentrations at LOR to command reported by Doufas et al. (10). Our result and others (15–17) suggest that the interaction between N2O and hypnotic drugs is antagonistic because the concentration of N2O alone required to prevent response to command in 50% of patients is 60%–70% (16).
The CP50LOR of propofol in our study was 4.58 μg/mL. Previous studies reported CP50LOR values of 2.32–4.4 μg/mL (1–8), depending on the study design. At the lower end of the range, Schnider et al. (5) reported a value of 2.32 μg/mL (effect-site concentration) in young volunteers tested by response to verbal command, whereas at the upper end of the range, Kazama et al. (4) reported a value of 4.4 μg/mL (arterial blood concentration) in surgical patients tested with a combined verbal/tactile stimulus. Our study design and CP50LOR estimate (4.58 μg/mL) are consistent with this higher value.
The amount of overlap in propofol concentrations between responders and nonresponders in the propofol-N2O group was similar to other studies (1–8). However, there was substantial overlap between responders and nonresponders, as well as several marked outliers, in the propofol-alone group. Therefore, the resulting concentration-response curve was less steep than the curve for propofol and N2O combined, and the 95% CIs around the estimate of CP50LOR were very wide. Interindividual pharmacodynamic variability (caused by chance or a small sample size), or inconsistent application of the verbal/tactile stimulus, would be expected to affect both groups similarly. Perhaps inclusion of a repeated tactile stimulus introduces a noxious element that is ablated by the analgesic effect of N2O.
In all studies of anesthetic potency, the ability of subjects to respond to command is used to define consciousness. However, the terminology used and timing of the assessment varies. For inhaled anesthetics, the minimum alveolar anesthetic concentration (MAC) at which 50% of patients respond to command is termed MAC-awake (18). The assessment is traditionally made during emergence (16), although it has been defined during the induction (15). For IV anesthetics, various terminologies have been used, including CP50-awake (2,7,8) and CP50loss of consciousness (1,3–5), and the assessment is usually made during the induction. We used the term CP50LOR because it precisely defined what was measured and does not imply anything about retention or recall of information (which may or may not be associated with responsiveness to command).
The BIS50LOR for propofol-alone that we report is consistent with previous studies (19,20), and adding 67% N2O significantly increased the BIS50LOR. Kearse et al. (20) reported a similar increase in the BIS50LOR with the addition of N2O (65.2 [95% CI, 62.9–67.6] versus 75.7 [95% CI, 71.2–80.1]), although their volunteers only inhaled 30% N2O. Thus, N2O is able to participate with propofol in the suppression of response to verbal and tactile stimulation without this effect being reflected by the BIS. Further confirmation of this phenomenon is found in the results of our regression analysis for predictors of BIS, namely, N2O was a significant univariate predictor of BIS values but was no longer a predictor when an adjustment was made for propofol concentration (propofol concentrations were larger and BIS values lower in the propofol-alone group compared with the propofol- N2O group).
N2O produces electroencephalographic (EEG) effects that are unique among known anesthetics (21) and alters some features of the EEG when added to potent inhaled anesthetics (22,23). However, N2O does not consistently affect current quantitative EEG indices, such as BIS (21,24) or entropy (25), when given alone or as a supplement to potent anesthetics, especially in the absence of noxious stimulation (24,26). Despite the utility of such indices in optimizing anesthetic depth and preventing complications (27,28), they rely on a series of heuristic criteria and not a physiological understanding of the EEG and, as such, may be blind to anesthetics with unusual electrophysiological effects.
The target-controlled infusion produced acceptable stability in arterial blood concentrations; however, the device substantially over-achieved the target concentration, especially in the propofol-N2O group. This result is consistent with our previous reports (7,8) and those of others (29,30) but is inconsistent with earlier work that reported better performance (31). There are several possible explanations for this result. First, our patient population may have exhibited more than usual interindividual pharmacokinetic variability because of chance or small sample size. However, our sample size (n = 39) was similar to other studies. Second, technical difficulty with blood sampling, such as temporary venous or infusion line obstruction resulting in purging of propofol just before sampling, may have occurred (although no such technical difficulties were evident in our study). Third, our assay may have systematically overestimated the propofol concentration, although all quality variables for the assay were acceptable and the CP50LOR estimates were credible (1–8). Finally, the Marsh et al. (11) pharmacokinetic data set may not accurately reflect propofol pharmacokinetics in our patient population.
However, there were no significant differences in performance errors between the two groups, and so the overlap of propofol concentrations in responders and nonresponders in the propofol-alone group could not be attributed to increased bias and inaccuracy of the target-controlled infusion. In fact, the trend was in the opposite direction, with higher median values for performance errors in the propofol-N2O group.
In conclusion, N2O (67%) decreased the CP50LOR of propofol by 43% in healthy surgical patients. The BIS50LOR was increased in patients receiving propofol and N2O compared with those receiving propofol alone.
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