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© 2001 International Anesthesia Research Society
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Abstract |
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Recently it was reported that the pharmacokinetics of propofol are modified by changes in cardiac output. The objective of this study was to evaluate the effects of cardiac output and other factors on the hypnotic dose of propofol. One-hundred surgical patients were administered indocyanine green immediately before the induction of anesthesia to measure their cardiac outputs and blood volumes. Propofol (250 µg · kg-1 · min-1) was infused IV for 8 min, and the hypnotic dose of propofol and the time to hypnosis were recorded. The plasma concentration of propofol immediately after 2 mg/kg infusion was measured. Multiple regression analysis showed that, in addition to age and weight, cardiac output was a small but significant factor for predicting the hypnotic dose of propofol (R2 = 0.468, P < 0.001), the time to hypnosis (R2 = 0.454, P < 0.001), and the plasma concentration of propofol (R2 = 0.248, P < 0.01). Cardiac output, age, and weight showed similar partial coefficients for the hypnotic dose (0.128, 0.137, and 0.140, respectively).
Implications: This study demonstrates a significant relationship between cardiac output and the hypnotic dose of propofol. We suggest that anesthesiologists should include cardiac output, as well as age and weight, in calculating the induction dose of propofol.
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Introduction |
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Many investigators have extensively studied the hypnotic dose of propofol during the induction of anesthesia, and a variety of factors affect the dose required to achieve hypnosis. These included patient’s age (1–4), sex (1), body weight (1,5,6), the rate of infusion (7), coadministered drugs (8), and anxiety (9). These phenomena can be partly explained by their effects on pharmacokinetics, which modulate the concentration of propofol (1,7). The plasma or central compartment concentration of propofol can be predicted by using a compartmental pharmacokinetic model (10,11), and many anesthesiologists apply such a model in the clinical settings (e.g., for target-controlled infusion techniques) (12). Usually a pharmacokinetic model of propofol concentration contains only the patient’s body weight as a covariate (10,11). Other covariates, however, might also be important for predicting the concentration of propofol.
Avram et al. (13) suggested that the pharmacokinetics of IV anesthetics depended on their initial disposition. Upton et al. (14) reported that cardiac output is a determinant of the initial concentration of propofol after the administration of a short IV infusion. The cardiac output at the induction of anesthesia will vary among patients because it is regulated by numerous factors. Thus, we hypothesized that the cardiac output at the induction of anesthesia would be a major determinant of the hypnotic dose of propofol. A method for measuring noninvasively the blood concentration of indocyanine green (ICG) by using pulse spectrophotometry has recently been developed. This method can be used for measuring cardiac output (15) and blood volume (16) easily and accurately in the operating room (OR) without any additional catheterization or monitoring. The aim of this study was to evaluate the effects of circulatory variables, including cardiac output and blood volume, as measured by spectrophotometry immediately before the induction of anesthesia, on the hypnotic dose of propofol and the time to hypnosis during the induction of anesthesia.
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Methods |
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After the study protocol had been approved by the institutional ethics committee, written informed consent was obtained from 100 patients. The patients were men and women, aged 15–83 yr, ASA physical status I or II, scheduled for elective surgery under general anesthesia and orotracheal intubation. Patients were excluded from the study if 1) they had any significant cardiovascular, respiratory, hepatic, or renal disease; 2) they were receiving medications known to affect central nervous system activity; or 3) they had neurological or allergic complications. All patients were premedicated with hydroxyzine (1 mg/kg IM) and atropine sulfate (10 µg/kg IM) 30 min before arriving in the OR.
Before the induction of anesthesia, 0.4 mg/kg of 0.25% ICG solution was rapidly administered into a peripheral vein, followed by flushing with 20 mL saline. The probe of the integrated pulse spectrophotometry monitoring system (DDG1001; Nihon Kohden Inc, Tokyo, Japan) was attached to the patient’s thumb. Measurement of the cardiac output and blood volume was usually completed within 6 min (15,16). The rate of plasma ICG disappearance, k [CICG(t) = CICG(0) · e-kt] was computed by linear regression from the semilogarithmic plot of ICG concentration versus time from approximately 2 min to 6 min after injection, where CICG(t) = ICG concentration at t minutes after injection and e = natural logarithm (16). Mean transit time (MTT) was calculated with the following formula:
MTT = 
(Cn · Dtn · tn)/(Cn · Dtn)
where Cn = ICG concentration at nth time interval, Dtn = time interval (taken as 16 ms in this study), tn = time from the injection of ICG until concentration Cn is recorded, and n = 1, 2, 3 ... . (16). Then, propofol was infused IV for 8 min at a constant rate of 250 µg · kg-1 · min-1.
The depth of hypnosis in each patient was assessed every 10 s beginning 2 min after starting the propofol infusion. Complete hypnosis was defined as a failure to open their eyes in response to a verbal command or to respond to a light tactile stimulus by the anesthesiologist in charge. For four patients, who continued opening their eyes slightly, a loss of response in the eyelash reflex was defined as the hypnotic end point.
After hypnosis was achieved, vecuronium bromide (0.12 mg/kg) was administered, and the propofol infusion was continued up to a total dose of 2 mg/kg. A 2-mL blood sample was then collected from the left femoral artery for the assay of the plasma concentration of propofol. Simultaneously, the trachea of the patient was intubated, and general anesthesia was continued with propofol and fentanyl according to our routine procedures.
The hypnotic dose of propofol, the time to hypnosis, noninvasive blood pressure measurement, and heart rate were recorded at the beginning of induction, at the time of achieving hypnosis, and immediately before and after orotracheal intubation. Blood samples were centrifuged at 3500 rpm for 30 min and the plasma frozen and stored until assay. All assays were performed within 1 mo.
The plasma concentration of propofol was determined with high-performance liquid chromatography, with fluorescence detection at 310 nm after excitation at 276 nm (RF550; Shimadsu, Kyoto, Japan). The areas under the chromatographic peaks were calculated with an integrator (PowerChrom; ADInstrument, Tokyo, Japan). Propofol concentrations were estimated on the basis of the peak area ratio of propofol to the internal standard, thymol. Linear relationships were obtained between propofol to the internal standard peak area. The correlation coefficient was in excess of 0.997 in the range from 50 ng/mL to 10 µg/mL (seven points of the concentration). The detection limit of propofol was 10 ng/mL by this assay. The coefficients of variation were 4.6% and 2.1% for concentrations of 1 and 10 µg/mL. The between-day coefficient of variation was 2.2% for a propofol concentration of 10 µg/mL.
The age, sex, weight, height, and cardiovascular variables—including the cardiac output, MTT, heart rate, blood volume, and k value—were used as independent variables in a multiple regression analysis. Another regression model included lean body mass (LBM) (17) instead of total body weight. The dependent variables were the hypnotic dose of propofol, the time for achieving hypnosis, and the plasma concentration of propofol immediately before intubation. We used McHenry’s select algorithm (18) for selecting the subset that provided the maximum value of R2. The correlation between two variables was evaluated by using a linear regression model as appropriate. This model was considered appropriate for explaining the effect of each independent variable on dependent variables. A value of P < 0.01 was considered statistically significant. Data are presented as mean ± SD. Statistical analysis was performed with the statistical software package NCSS 2000 (Number Cruncher Statistical Systems, Kaysville, UT).
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Results |
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Complete data sets were obtained from 92 patients. In eight patients, the spectrophotometric measurement of the cardiac output or blood volume failed because the measurement was disturbed by unpredictable movements of a patient’s hand or by baseline drifts in spectrophotometry (15). Results from these eight patients were excluded from analysis. Patient characteristics and the results of measurements in the 92 patients are shown in Table 1.
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Table 2 shows the results of multiple regression analysis with total body weight as an independent variable. The four variables—patient’s age, weight, cardiac output, and k value—were significant predictive variables for the dose of propofol (in milligrams) required for hypnosis (R2 = 0.468, P < 0.0001) and the time for achieving hypnosis (R2 = 0.454, P < 0.0001) ( Fig. 1). The plasma concentration of propofol immediately after the administration of 2 mg/kg was best predicted from age, weight, and cardiac output, but not from the k value (R2 = 0.248, P < 0.0001). With increasing patient age, the hypnotic dose of propofol decreased, the time for achieving hypnosis shortened, and the plasma concentration of propofol increased. Patient’s weight was positively correlated with the hypnotic dose of propofol and the plasma concentration of propofol, and negatively correlated with the time for achieving hypnosis. As the cardiac output increased, the hypnotic dose of propofol and the time for achieving hypnosis increased, and the concentration of propofol at intubation decreased. Table 3 shows the results of regression analysis with LBM instead of total body weight. When LBM was used as an independent variable instead of total body weight, the regression analysis showed similar results about the dose of propofol (in milligrams) required for hypnosis. LBM was not selected, however, as a predictive variable for the time to hypnosis and the concentration of propofol. Multicollinearity among independent variables was rejected in all models because the variance inflation factor [1/(1 - R2j)] was <10 and because all the condition numbers of the eigenvalues of centered correlations were <10.
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Discussion |
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In addition to other factors, we assessed the effect of cardiac output on the dose of propofol required for achieving hypnosis during the induction of anesthesia. Multiple regression analysis showed that cardiac output, as well as patient’s age and weight, was significantly correlated with the hypnotic dose of propofol, the time for achieving hypnosis, and the plasma concentration of propofol immediately after the infusion of 2 mg/kg propofol. The mean plasma concentration of propofol in the present investigation (3.69 ± 1.09 µg/mL) showed a good agreement with the value calculated with the conventional compartmental pharmacokinetic models described by Marsh et al. (10) of 3.8 µg/mL and by Gepts et al. (11) of 4.3 µg/mL. These models incorporate only weight as a covariate. However, our results suggested that other physiological factors were also important for determining the propofol induction dose. Schnider et al. (19) described a three-compartment mammillary model for propofol that included age, sex, weight, height, and LBM as covariates. The mean plasma propofol concentration after an infusion of propofol 2 mg/kg predicted by the Schnider model in our patients was 4.34 ± 0.70 µg/mL. Although the concentrations predicted by the Schnider model were statistically different from our measured concentrations (paired t-test), there was a significant correlation between them (R2 = 0.153, P < 0.001). Moreover, when cardiac output was added as a covariate in the regression model, the value of R2 increased to 0.302 (P < 0.0001):
Measured concentration (µg/mL) = 1.77 + 0.75 · simulated concentration - 0.27 · cardiac output (L/min).
The bias (the intercept of the regression model) might be explained by the different populations in the two studies.
Elderly patients require a smaller dose of propofol for achieving hypnosis or anesthesia (2,3,19) and are more sensitive than younger patients to hypnotic drugs and the electroencephalogram effects of propofol (3). A patient’s age has little affect on the required dose of propofol for hypnosis (1,4) or other propofol effects (2). The results of the present investigation, however, suggest that age has significant effects on the hypnotic dose of propofol, the time for achieving hypnosis, and the plasma concentration of propofol immediately before intubation. The significant correlation between age and the concentration of propofol suggests that the pharmacokinetics of propofol were different between elderly patients and young patients. This is in agreement with the results reported by Schnider et al. (19). Our findings of a significant correlation between age and the hypnotic dose or the time to hypnosis confirm other evidence (3) that the pharmacodynamics of propofol might be different between older and younger patients.
Propofol was administered to patients in this study at a constant infusion rate that was based on individual total body weight. However, not only the required dose of propofol in milligrams, but also the time for achieving hypnosis, were significantly affected by patient weight, despite our adjusting the infusion rate according to body weight. Heavy patients required a larger hypnotic dose of propofol than light patients, whereas the time for achieving hypnosis, and thus hypnotic dose per kilogram, was less in heavy than in light patients. Two studies demonstrate that propofol requirements for the induction of anesthesia are proportional to the LBM rather than the total body weight (1,6). Our results are consistent with and support this finding. The plasma concentration of propofol was larger in heavy patients, and this relationship agrees with the results of Hirota et al. (5). Lind et al. (20) also stated that the induction dose of propofol predicted by total body weight should be reduced in obese patients. In their study, an infusion rate based on total body weight resulted in overdosing of heavy patients. When LBM was used as an independent variable for the regression model instead of total body weight, LBM was not selected for the predictive variables for the time to hypnosis and the plasma concentration of propofol. These findings were consistent with other investigations (1,5,6), although the infusion rate of propofol was based on total body weight in the present investigation.
In addition to age and weight, cardiac output was also identified as an important predictive variable for the hypnotic dose of propofol during the induction of anesthesia. Patients who had higher cardiac outputs required larger doses of propofol for hypnosis. A traditional pharmacokinetic compartment model does not include cardiac output as a variable for calculating or predicting drug concentration (10,11,21,22). Recently, cardiac output was reported as a determinant of the initial concentration of propofol after a short infusion (14). Cardiac output is a determinant of the volumes of central and peripheral compartments (23). We demonstrated that this physiological variable might affect the pharmacokinetics or pharmacodynamics of propofol for inducing hypnosis. For a given dose, the plasma concentration of propofol will be larger in a patient with a low cardiac output than in a patient with a high output. If the dose of propofol is calculated only on the basis of a patient’s age and weight, without taking a possible low cardiac output into consideration, potentially dangerous hypotension may be induced because propofol-induced circulatory depression occurs more slowly than hypnosis (4). Avram et al. (24) reported that the induction dose of thiopental was independent of cardiac output when using an electroencephalogram end point. We have no explanation for the difference between the results. The differences of pharmacokinetics or pharmacodynamics between propofol and thiopental or the difference of methodology might be responsible factors for the inconsistent results.
The rate of plasma ICG disappearance (k) measured by spectrophotometry was found to be a significant predictive variable for the required dose of propofol and the time for achieving hypnosis. This k value is often used to assess hepatic blood flow (25). Because hepatic blood flow is related to cardiac output (25), the k value might be dependent on the cardiac output. There was no multicollinearity among any of the predictive variables used in our study, and hepatic clearance of propofol represented as k value was considered an important factor for predicting the plasma concentration of propofol. The k value was not a significant predictive factor for the regression model for predicting the plasma concentration of propofol immediately after the administration of propofol 2 mg/kg when total body weight was used. Although this was considered consistent with the findings of Schnider et al.(3), who demonstrated that the metabolic clearance of propofol exceeded the hepatic blood flow, the effect of metabolism is uncertain for a short period at the beginning of the induction of anesthesia. Propofol undergoes extensive uptake and first-pass elimination in the lungs of sheep (26). Further investigation was needed to clarify this point.
Several limitations must be addressed concerning the design of this investigation. We determined the required dose of propofol and the time to hypnosis during the induction by using a constant rate infusion of propofol. Target-controlled infusion techniques have been used (12), and hypnosis is assessed after equilibration of the concentration of propofol between blood and the effect site (3,4,19). In a usual practical setting in an OR, however, the anesthesiologist tends to administer a drug incrementally until the appearance of the required clinical effect (9). Our protocol with a fixed low infusion rate of propofol will result in a gradual increase in propofol concentration and thus should be more sensitive to changes in the hypnotic dose of propofol (27). However, we did not examine the effect of the infusion rate. There is a possibility of different results at different infusion rates or for different end points (28). Cardiac output changes during the induction of anesthesia (4), but the cardiac output measured immediately before starting propofol infusion showed a significant correlation with the hypnotic dose, time to hypnosis, and the concentration of propofol, and these might be important findings.
In summary, we have demonstrated that cardiac output is a small but significant predictive variable for the hypnotic dose of propofol, the time for achieving hypnosis, and the plasma concentration of propofol shortly after the induction of anesthesia. Other predictive variables are age and weight. Anesthesiologists need to take these factors, including the hemodynamic status of the patient, into account when determining the appropriate dose of propofol for the induction of anesthesia.
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Acknowledgments |
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We express our thanks to Dr. K. Okamoto and Prof. J. Okamoto for reviewing and commenting on this manuscript.
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