Drug effect lags behind the blood concentration. The goal of this investigation was to determine the time course of plasma concentration and the effects of propofol demonstrated by electroencephalogram or blood pressure changes and to compare them between elderly and young or middle-aged patients.
A target-controlled infusion was used to rapidly attain and maintain four sequentially increasing, randomly selected plasma propofol concentrations from 1 to 12 microg/ml in 41 patients aged 20-85 yr. The target concentration was maintained for about 30 min. Bispectral index (BIS), spectral edge frequency, and systolic blood pressure (SBP) were used as measures of propofol effect. Because the time courses of these measures following the started drug infusion showed an exponential pattern, the first-order rate constant for equilibration of the effect site with the plasma concentration (k(eO)) was estimated by fitting a monoexponential model to the effect versus time data resulting from the pseudo-steady-state propofol plasma concentration profile.
The half-times for the plasma-effect-site equilibration for BIS were 2.31, 2.30, 2.29, and 2.37 min in patients aged 20-39, 40-59, 60-69, and 70-85 yr, respectively (n = 10 or 11 each). The half-times for SBP were 5.68, 5.92, 8.87, and 10.22 min in the respective age groups. All were significantly longer than for BIS (P < 0.05). The propofol concentration at half of the maximal decrease of SBP was significantly greater (P < 0.05) in the elderly than in the younger patients.
The effect of propofol on BIS occurs more rapidly than its effect on SBP. Age has no effect on the rate of BIS reduction with increasing propofol concentration, whereas with increasing age, SBP decreases to a greater degree but more slowly.
Key words: Aged patients; keO; pharmacodynamics.
THE drug concentration time course in plasma cannot in itself predict the time course or magnitude of drug effect because plasma is not the effect site for most drugs. The site at which a drug produces its effect is termed the biophase. There is also a time lag between the blood and the actual effect-site concentrations because of the hysteresis between blood and the biophase. This lag between plasma concentration and effect suggests the necessity for calculating the keOparameter, which is the rate constant describing the elimination of drug from the effect-site compartment.
Although measuring absolute effect-site concentration is not feasible, we can measure the drug effect within the central nervous system using an electroencephalogram (EEG). The EEG usually exhibits a biphasic response to increasing thiopental concentration; that is, there is activation followed by slowing of the EEG waveforms. [4,5]This phenomenon has confounded attempts to predict anesthetic effect using EEGs, as one EEG variable value may be associated with two different anesthetic concentrations. [4,5]The bispectral index (BIS), which is derived from the EEG, incorporates features designed to overcome this problem.
Reduction in systolic blood pressure (SBP) often occur during induction of anesthesia with propofol. [6-8]Cardiovascular depression is rather pronounced in the elderly and is also influenced by the dose and rate of propofol administration. [9,10]However, there are few reports concerning the relationship between the time course of concentration and the effect of propofol. Furthermore, the time course of hypnotic and hemodynamic effects of propofol has not yet been investigated precisely in the elderly compared with that in younger patients.
The first part of the study was designed to determine the pharmacodynamics of propofol, as measured by the BIS or blood pressure. We used a target-controlled infusion system to overcome the delay and impediments arising from the rapid distribution pharmacokinetics of propofol. The second part of the study was designed to investigate keO, the rate constant describing the elimination of drug from the effect-site compartment, and to compare keOdeterminations in young to middle-aged and elderly patients.
Materials and Methods
The study was approved by the Hamamatsu University Hospital Ethics Committee. After obtaining written informed consent, we studied 11 patients aged 20-39 yr (group 1), 12 patients aged 40-59 yr (group 2), 12 patients aged 60-69 yr (group 3), and 12 patients aged 70-85 yr (group 4) who were undergoing elective surgery. All patients had American Society of Anesthesiologists physical status I or II, with no known or suspected cardiac, pulmonary, liver, renal, or metabolic disease. Patients with significant obesity (body mass index > 30) or with neurologic dysfunction were excluded from the study. No premedication was given prior to the experiments. After overnight fasting, the patients were brought to a quiet surgical operating room where, after the patients were given local anesthesia, a cannula was inserted into an antecubital vein for the infusion of propofol and for fluid replacement (Ringer's lactate solution of 5 ml [middle dot] kg-1[middle dot] h-1). A radial arterial catheter was inserted for measuring blood pressure and sampling blood. Heart rate, blood pressure, ECG, end-tidal carbon dioxide, rectal temperature, and oxyhemoglobin saturation were monitored continuously throughout the study. Body temperature was maintained at 36-37 [degree sign]C using a forced-air warming blanket (Bear Hugger, Augustine Medical, Eden Prairie, MN). Oxygen was administered through an anesthesia mask during the study, and spontaneous respirations were manually assisted when necessary to keep arterial carbon dioxide tension within physiologic range.
After skin preparation, silver/silver chloride gel-filled electrodes were secured to the left and right frontal pole regions and referenced to a central vertex electrode. Impedance was maintained at less than 3 k Omega, and EEG was recorded and analyzed using an A1000 EEG monitor (software version 3.12, Aspect Medical Systems, Natick, MA). Baseline BIS, spectral edge frequency 95% (SEF95), and SBP were recorded for at least 5 min. The subjects kept their eyes closed, and no type of stimulation, including verbal command, was permitted during the study.
Target-controlled Infusion for Propofol
Rapid attainment and maintenance of constant plasma concentrations for intravenous anesthetics can be achieved with target-controlled infusion (TCI). [11-13]Propofol was delivered using a pharmacokinetic model-driven infusion device designed for TCI. The system consisted of an NEC (Tokyo, Japan) 9821 microcomputer interfaced to an Atom (Tokyo, Japan) syringe pump (model 1235) utilizing a three-compartment model with central elimination. The control software was programmed in Turbo Pascal (Borland International, Scotts Valley, CA) by one of the authors. Details were described in our previous report. The pharmacokinetic parameters used were reported by Gepts et al. for patients aged 20-64 yr and by Oostwouder et al. for patients older than 65 yr.
A blood sample was drawn before drug administration. After the beginning of propofol infusion, samples were collected at 0.5, 1, and 2 min. Then samples were taken every 2 min until EEG recording was terminated. Infusion time of each target concentration was about 30 min. Four sequentially increasing, randomly selected target concentrations from 1 to 12 [micro sign]g/ml were studied in each patient.
TCI Pump Performance Analysis
To characterize the success in achieving the target plasma propofol concentrations, the percent performance error (PE) was defined as Equation 1where CMwas the measured plasma propofol concentration from 22 to 30 min after start of infusion and CTwas the predicted target concentration. The median PE for the population was then calculated as the median of all individual median PEs. The population median PE is a measure of the systematic bias by the TCI. The median absolute PE for the population was calculated as the median of all individual median absolute PEs. To define the constant plasma concentrations, the percentage of change in individual mean stable plasma concentrations obtained from 22 to 30 min after the start of infusion was calculated. Any patients whose measured plasma propofol concentrations at 0.5 and 1.0 min after initiation of propofol infusion were not within 30% of their own individual equilibrated concentrations were excluded from analysis of the pharmacodynamics and keOs related to EEG change or blood pressure. Patients whose propofol concentrations from 2.0 to 30 min after infusion were not within 10% of their individual mean plasma concentrations were also excluded.
Multiple Target Level Study
A TCI system was used to rapidly attain and then maintain four sequentially increasing, randomly selected propofol concentrations from 1 to 12 [micro sign]g/ml. When an excessive level of anesthesia occurred, the study was terminated even if the four steps were not completed. Signs of an excessive anesthesia were defined as follows: (1) SBP less than 80 mmHg in patients aged fewer than 60 yr or less than 90 mmHg in patients aged more than 60 yr; (2) heart rate less than 50 beats/min. The target concentrations were maintained for about 30 min each to attain equilibration between blood and effect-site. If the BIS and SBP reached a constant state, they were deemed to indicate an equilibrated state between blood and effect-site. It was not possible to "step down" the concentrations because of the additional time necessary to allow the propofol concentration to decline.
Blood plasma samples were separated immediately and stored at 5[degree sign]C on ice until extraction and assay. Within 12 h after sampling, plasma concentrations of propofol were determined using high-performance liquid chromatography with fluorescence detection at 310 nm after excitation at 276 nm (CTO-10A, RF550, and C-R7A, Shimadsu, Kyoto, Japan). For each batch of blood samples, a standard curve was computed by adding pure propofol liquid to drug-free human plasma to achieve concentrations of 1.0, 5.0, 10.0, and 15.0 [micro sign]g/ml. Linear regression (least-squares method) was used with plasma propofol concentration as the dependent variable. Propofol concentrations in this study were calculated using the obtained regression equation. The lower limit of detection was 15 ng/ml, and the coefficient of variation was 7.4%.
Intubation was facilitated by vecuronium, 6 mg, after completion of measurement of BIS, SEF95, and SBP at the individual tested highest target propofol concentration.
Propofol Pharmacodynamic Modeling
When BIS or SBP values were constant for 5 min after equilibration, we considered the plasma propofol concentration to be equivalent to that at the effect-site.
We assumed that the relationship between concentration and effects on EEG or SBP could be described with a sigmoidal Emaxmodel as described by Hill: Equation 2in which E0was the effect with no drug, Emaxwas the maximal predicted difference from baseline effect, IC50was the concentration associated with 50% of maximal effect, and [Greek small letter gamma] (sometimes called the Hill coefficient) determined the steepness of the concentration versus response relationship. Ce(t) was the "effect-site" concentration. We expressed the effects on SBP as the percent SBP decrease from baseline to 80 mmHg: Equation 3
The parameters IC50and [Greek small letter gamma] were fitted to the data with use of least-squares regression.
To assess the accuracy of the model, the coefficient of correlation r2between observed effect (Eobs) and predicted effect (Epred) was calculated according to classic formula: Equation 4
Determination of keO
Effect-site concentration (Ceffect[t]) was calculated as the convolution of the plasma concentration over time with the disposition function of the effect site. Equation 5If plasma propofol concentration (Cplasma[t]) is constant, then the above Equation canbe simplified as follows: Equation 6And if the effect is linearly related to concentration, then the effect itself can be modeled as follows: Equation 7Both BIS and SEF95 have been used as EEG measures of propofol drug effect. [18-20]SBP was used as hemodynamic effect of propofol. The parameters of keO, a and b were fitted by least-squares regression (SigmaPlot, Jandel Scientific, San Rafael, CA) to each of the decreasing time course data of BIS, SEF95, and SBP after each multiple target propofol concentration.
There is a delay between the change of target propofol concentration and measured BIS and SEF95, which includes a lag time of about 1 min between making a change in target concentration and exposing the brain to this step change, and an inherent time delay between the actual EEG and measured BIS and SEF95 (Figure 1). Time 0 with the change of real BIS and SEF95 actually represents 1.0 min, which is the lag of TCI, after a change in target concentration. Measured BIS and SEF95 values are calculated by a 0.5-min rolling window and are displayed at the last point of the 0.5-min rolling widow. Because the measured BIS or SEF95 values should be at the midpoint of the 0.5-min rolling window, the measured BIS and SEF95 values are delayed by 0.25 min after actual EEG. Consequently, the start of measured BIS or SEF95 change was 1.25 min after each new target step (Figure 1).
To obtain keOs, the model fitting to measured BIS or SEF95 starts 0.25 min after the start of measured BIS or SEF95 change to exclude the data containing EEG effects before the change of plasma propofol concentration (Figure 1).
Propofol induced an activation in fast frequencies initially. [18,21]The existence of EEG activation at the first or second step was inspected on each patient's SEF95 data. The keOs were estimated separately with EEG activation or non-EEG activation, because the activation of EEG may influence the keOof BIS or SEF95.
The IC50and mean values of the half-time of equilibration (t (1/2) keO), which is the ln(2)/keO, were compared between all four groups. Statistical analysis included analysis of variance with Bonferroni multiple comparison tests used to assess differences between groups. A P value < 0.05 was considered statistically significant.
All studies were completed without clinically significant complications. No significant differences were found between the groups with respect to sex ratio, weight, and height (Table 1). Not all the patients received propofol at all four steps because of excessive anesthesia levels (Figure 2). Specifically, the patients of group 4 could not receive propofol at concentrations greater than 8 [micro sign]g/ml (Figure 2).
One patient each from groups 1 and 3 and two patients each from groups 2 and 4 were excluded from the analysis of the pharmacodynamics and k (eO) s on EEG change or blood pressure because their measured plasma propofol concentrations at 0.5 and 1.0 min after initiation of propofol infusion were not within 30% of their own individual equilibrated concentrations, or their propofol concentrations from 2.0 to 30 min after infusion were not within 10% of their individual equilibrated concentrations.
There was a strong correlation between measured equilibrated plasma propofol concentration and target concentration (r = 0.973). The median PE (bias) of the TCI in all subjects was 22.3%, and the median absolute PE (accuracy) was 22.9%. Figure 3depicts the percent change in individual mean stable plasma concentrations versus time profiles. In each group, with the propofol pharmacokinetic parameters used in the TCI, it was possible to obtain constant plasma concentrations. Following a step change in target propofol concentration, the plasma concentration of propofol increased immediately with a slight "overshoot" to a level that is less than 30% of the final equilibrated propofol concentration, and it then remained at the pseudo-steady-state target concentration (Figure 3).
When the concentration of propofol was less than 2 [micro sign]g/ml, the decrease in BIS was slight (Figure 4). In concentrations greater than 2 [micro sign]g/ml, BIS decreased as propofol concentration increased (Figure 4). The IC50s of BIS were not significantly different between the age groups tested (Table 2). SBP decreased as propofol plasma concentration increased (Figure 5). The IC50of SBP in group 4 is significantly smaller than those of the other groups (Table 2). The SEF95 did not decrease linearly as propofol plasma concentration increased, and the decreases in SEF95 were small in concentrations greater than 2 or 4 [micro sign]g/ml (Figure 6).
Bispectral index, SEF95, and SBP stabilized gradually (Figure 7) after each new target concentration was set. This lag between plasma propofol concentration and BIS or SBP stabilization suggests the necessity for determining the keOparameters of our model. At the beginning of the second step, 21 patients showed an increase in SEF95, which was associated with an unchanged BIS value (Figure 8, Table 3). For the second step in 20 other patients and for the third or fourth step in all patients, increases in SEF95 were hard to distinguish. The t1/2keOs of equilibration between the plasma and the site of drug effect with BIS, SEF95, and SBP, are shown in Table 3. The t1/2keOof SEF95 in the third or fourth step could not be defined because the decreases of SEF95 values were not enough to estimate keO(Figure 6).
In elderly patients, EEG activation defined with SEF95 increase was observed more frequently in the first step than in the second step (Table 3). The mean t1/2keOof the BIS were not significantly different between the age groups tested. The t1/2keOs of BIS at the step with EEG activation were significantly longer, from 1.6 to 1.8 times (P < 0.05), than those without EEG activation. The mean t1/2keOs of the SBP increased with age. The t1/2keOs of SBP with or without EEG activation were the same. The mean t1/2keOs of SBP were about 2.5 times longer than those of the BIS at the steps without EEG activation in patients younger than 60 yr. In patients more than 60 yr old, the t1/2keOs of SBP were about four times longer than those of the BIS.
The rate of decrease of BIS was almost the same in both the young and elderly. SBP decreased more in the elderly than in the younger patients, although the rate of decrease was slower in the elderly.
The primary goals of this study were to develop a methodology that would allow rapid achievement of constant plasma propofol concentrations that result in a stable drug effect and to define the pharmacodynamic effects of propofol apparent on measures of BIS and blood pressure.
The pharmacokinetic parameters we used in TCI were based on whole-blood propofol concentration. The median PE between plasma and target propofol concentration in our TCI was 22.3%, which may derive from the 30% difference between whole-blood and plasma propofol concentration. However, the TCI in our study worked very well in maintaining stability of concentrations in both the young and the elderly by using two different pharmacokinetic sets based on age. When drug concentrations at the effect-site have reached equilibrium and the response is constant, the concentration-effect relationship is known as the drug pharmacodynamics. In our study, both the BIS and SBP reached stable states.
The other goals of this study were to define the sensitivity and the keOs of propofol as measured by the BIS or SBP.
Residual Errors of keODefined with BIS Decrease
It is possible that BIS may not reflect the change of real EEG precisely because BIS is a 30-s rolling window providing an inherent delay in the value that is being read. Figure 9, A and B show the prediction error between estimated keO(30-s rolling window) and the keOof real BIS change (0-s rolling window) at estimation from a short sampling time (6 min; Figure 9A) and a long sampling time (30 min; Figure 9B). Prediction error was calculated as follows: Equation 9For various rates of BIS decrease expressed by keOfrom 0.05 to 2.00 min-1, prediction error was larger in short-sampling durations (Figure 9A) than in long-sampling durations (Figure 9B). When the data of the first 30 s from the start of real BIS change are excluded, the prediction error is almost none despite the duration of sampling time. In our study, the exclusion of the data of the first 30 s to obtain the keOvalue confirms its precision.
Differences in Onset of Propofol as Measured by the BIS
Bispectral index has been shown to decrease linearly as propofol blood concentration increases. [20,23]In our study BIS was not exactly linear with increasing propofol concentration, especially in concentrations less than 2 [micro sign]g/ml. We also could not calculate the keOof propofol on the BIS at concentrations between 0 and 2 [micro sign]g/ml. However, BIS showed enough linearity to calculate the keOat concentrations greater than 2 [micro sign]g/ml. Propofol induced an activation in fast frequencies, then a shift of the spectrum to low frequencies, and finally burst suppression. Sneyd et al. reported that [Greek small letter beta]1 activity in EEG was significantly increased at the concentrations of 0.679 and 1.065 [micro sign]g/ml but not in lower concentrations. Although the calculation algorithm of the BIS has been improved to account for EEG data recorded with different anesthetic drugs and to give better correlation to the hypnotic drug effects, [23,24]the biphasic EEG response of propofol may influence the time course of drug effect. Depending on the effect measure, Billard et al. reported that the t1/2keOvalues for delta power of EEG or BIS were 2.6 min or 3.3 min respectively using a monophasic sigmoidal Emaxmodel. Schnider et al. reported at t1/2keOof 2.2 min obtained with biphasic model of EEG change. We used the BIS to estimate the rate of plasma effect-site equilibration, and the EEG activation of propofol at the beginning of the second step slowed the rate of BIS decrease. The mean t1/2keOs of BIS decrease at the steps with or without EEG activation were about 3.8 or 2.3 min respectively in our study. Schnider et al. demonstrated that the EEG activation in older people occurs at lower concentrations but also that the transition from no effect to maximal activation is relatively gradual. These findings are consistent with ours that EEG activation in elderly was observed more frequently in the first step of target concentration than in the second step.
There was no significant relation between t1/2keOs of BIS in the EEG depression and age in our study. As for the relation between t (1/2) keOand age, there are no other reports dealing precisely with propofol. In thiopental, Stanski and Maitre reported that although the correlation of age to t1/2keOwas reported to be significant, the relation was extremely weak. They concluded that the effect of age is not clinically relevant.
Differences in Brain Sensitivity to Propofol as Measured by the BIS
The IC50s of BIS are not significantly different between the age groups tested in our study. Schnider et al. reported that brain sensitivity increased linearly by age in a loss-of-consciousness pharmacodynamic model. They also defined Cp50decreased as age with EEG activation phase and no change of Cp50as age with EEG depression phase by EEG pharmacodynamic model. For inhalational agents, an age-dependent increase in brain sensitivity has been reported. For thiopental, Stanski and Maitre and Homer and Stanski demonstrated that there was no effect of age on any of the pharmacodynamic parameters. The increased sensitivity to etomidate in the elderly was mainly accounted for by age-related pharmacokinetic changes. As for the brain sensitivity to propofol in rats, Larsson and Wahlstrom reported that young animals need a larger induction dose than old, but older animals had higher brain concentrations of propofol at the EEG endpoint than young, which means young rats are more sensitive than old rats as measured by the brain concentration of propofol. It remains unresolved whether the influence of age on brain sensitivity to propofol can be mainly accounted for by pharmacodynamic changes or pharmacokinetic changes.
Differences in Onset of Propofol as Measured by SBP
In our study, propofol plasma concentration attained a target concentration within 1 min. However, SBP decreased at a slower rate than plasma concentration. Claeys et al. reported that the arterial hypotension associated with the induction and infusion of propofol is mainly a result of a decrease in afterload without compensatory increases in heart rate or cardiac output. Ebert et al. demonstrated that the sympathoinhibition that occurs during propofol administration importantly contributes to the subsequent hypotension. In the report of Ebert et al., SBP decrease and sympathetic nerve activity attained maximal effect within 3 min after a bolus injection of propofol. Billard et al. reported that maximal predicted propofol biophase concentrations were achieved in 2.3 min. Using their unpublished data of t1/2keOfor hemodynamic effects of propofol as 5.9 min, they predicted the time to achieve the expected maximal effect in SBP after a bolus propofol infusion as 2.8 min, which is consistent with our t1/2keOvalue in those younger than 60 yr.
Differences in Sensitivity to Propofol as Measured by SBP
There are many reports of SBP reductions greater than 25% during induction of anesthesia with propofol, an effect manifested more in elderly than in younger patients. [10,33]In addition to the already reported pharmacokinetic parameters in elderly patients, [10,15]we found significant differences in the pharmacodynamics in the IC50s of pharmacodynamics on SBP between group 4 (older than 70 yr) and younger patients. This suggests that hypotension in the elderly patients younger than 69 yr is mainly a result of pharmacokinetic changes, and that hypotension in patients older than 70 yr is a result of pharmacodynamic changes in addition to pharmacokinetic changes.
The time courses of the BIS and SBP are important for understanding anesthesia status. In our study, although BIS decreased to the same degree at the same rate independent of age, SBP decreased more in elderly than in younger patients, and the rate of decrease was slower in the elderly. Considering our findings, to avoid delayed severe hypotension a lower induction dose and a slower maintenance rate of administration after loss of consciousness are suggested in the elderly than in other age groups.
In summary, we have investigated the effect of age on BIS and SBP change of propofol in humans. We found that the effect of propofol on BIS occurs more rapidly compared with the effect on SBP. The IC50of BIS did not change with increasing age. Age has no effect on the rate of BIS reduction with increasing propofol concentration, whereas with increasing age SBP decreases to a greater degree but more slowly.