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© 1999 International Anesthesia Research Society
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Abstract |
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Indicator dilution theory predicts that the first-pass pulmonary and systemic arterial concentrations of a drug will be inversely related to the cardiac output. For high-clearance drugs, these first-pass concentrations may contribute significantly to the measured arterial concentrations, which would therefore also be inversely related to cardiac output. We examined the cardiac output dependence of the initial kinetics of propofol in two separate studies using chronically instrumented sheep in which propofol (100 mg) was infused IV over 2 min. In the first study, steady-state periods of low, medium, and high cardiac output were achieved by altering carbon dioxide tension in six halothane-anesthetized sheep. The initial area under the curve and peak value of the pulmonary artery propofol concentrations were inversely related to cardiac output (
R2 = 0.57 and 0.66, respectively). For the systemic arterial concentrations, these R2 values were 0.68 and 0.71, respectively. In our second study, transient reductions in cardiac output were achieved in five conscious sheep by administering a short infusion of metaraminol concurrently with propofol. Cardiac output was lowered by 2.2 L/min, and the area under the curve to 10 min of the arterial concentrations increased to 143% of control.
Implications: The initial arterial concentrations of propofol after IV administration were shown to be inversely related to cardiac output. This implies that cardiac output may be a determinant of the induction of anesthesia with propofol.
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Introduction |
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The influence of cardiac output on pharmacokinetics has received little attention in the literature, in which cardiac output (CO) alone has generally been featured as a variable in multiorgan physiological models (1,2) and hybrid (3,4) and stochastic recirculatory models (5,6). Furthermore, although experimental evidence supports an influence of CO on kinetics (6–9), the number of drugs studied and the consideration of mechanisms have been limited.
A simple but useful analysis of the effect of CO on drug disposition can be achieved by considering the body to consist of two subsystems connected in a recirculatory manner (6,9)—the heart and lungs (with blood flowing from a right atrial drug injection site to the aorta), and the remainder of the body (with blood flowing from the aorta back to a right atrial drug injection site). After drug injection, any given drug molecule must make a first pass through the heart-lung subsystem before it can be measured in systemic arterial blood, and it must pass through one of the organs of drug clearance and distribution in the remainder of the body (the second subsystem) before it can recirculate and again be measured in arterial blood. These two processes, by definition, must occur sequentially, and it is useful to consider their mechanisms separately after an IV bolus or short infusion administration.
In the first pass through the heart-lung subsystem (ignoring, for the moment, the kinetics of the drug in the lungs), the drug is essentially added to a stream of blood flowing at a rate determined by the CO. The first-pass arterial concentrations emerging from the heart-lung system can be described by indicator dilution principles developed by physiologists to measure this type of blood flow (9,10), and it will have a shape similar to a dye curve (10) for CO measurement (Fig. 1). It is not possible to completely measure these first-pass arterial concentrations in vivo because, at some point, they become obscured by recirculated drug. However, the recirculated drug must have passed through the second subsystem. The longer the time required for this to happen (e.g., large distribution volumes leading to slow transit times through the body), the greater the contribution the first-pass concentrations will make to the measured arterial concentrations and the more likely they will be influenced by indicator dilution principles. Similarly, first-pass concentrations will become more significant the shorter the period for which blood is sampled in a study, and the greater the removal of drug from blood in its passage through the remainder of the body (e.g., high total body clearance).
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This argument can be formalized to facilitate the analysis of the effect of altered CO on the arterial area under the curve (AUC) after a bolus or short infusion drug administration. Consider that the first pass area under the pulmonary artery or systemic arterial concentration-time curves (AUCfirst) will be a function of dose and CO.
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Complicating factors for this analysis include the influence of lung kinetics. Although the first-pass pulmonary artery concentrations of a drug should be described by Equation 1, uptake of a drug into the lung (due to distribution and/or metabolism) will produce first-pass concentrations in arterial blood emerging from the lungs that are lower than those in the pulmonary artery blood entering the lungs. If the uptake is first-order, the uptake would increase the intercept, but not affect the slope, of an inverse plot. In addition, the concentration difference across the lungs could be used to make inferences about lung kinetics.
Another complicating factor is present when the Cl is also dependent on CO and is therefore a fixed fraction (Fcl) of CO.
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This analysis suggests two mechanisms by which the initial AUC of a drug would be dependent on CO. The first would be for drugs with a high Cl (Equation 4) or with slow recirculation times (large distribution volumes), in which first-pass concentrations predominate for a relatively long time in the study period. The second is for drugs in which clearance is dependent on CO and the clearance is a high fraction of CO (Equation 5).
Both mechanisms may therefore occur for drugs having a high Cl. Our previous experience with the IV anesthetic propofol in sheep has suggested that it has a high Cl in this species (13). After bolus or short infusion administration of propofol, it could be hypothesized that both mechanisms would operate "in series," resulting in a dependence of initial AUC (and therefore peak concentrations) in arterial blood on CO. This would be important for the induction of anesthesia with propofol if these altered arterial concentrations were also reflected in altered brain concentrations of propofol.
Therefore, we report two studies that examine the relationship between the initial concentrations of propofol and CO. In both studies, 100 mg of propofol was infused IV over 2 min to chronically instrumented sheep. In the first study, sheep were anesthetized, and CO was altered by changing ventilatory rate and inducing hypo- or hypercapnia. One goal of this study was to determine to what extent the initial pulmonary artery concentrations of propofol were inversely related to CO, and the slope of an inverse plot approached the theoretical maximum of 1/Dose. No influence of CO would produce a slope of zero. In addition, we sought to determine whether this CO dependence also applied to the systemic arterial concentrations of propofol despite the uptake and elution of propofol in the lungs.
In the second study, the sheep were conscious, and CO was transiently altered using a concurrent infusion of a sympathomimetic vasoconstrictor (metaraminol). The aim of our second study was to determine whether transiently lowering the CO during a short infusion of propofol produced higher propofol concentrations in systemic arterial blood and the brain, consistent with the general predictions of Equation 1.
An understanding of the influence of CO on the initial kinetics of propofol would be of practical significance to anesthesiologists. Patients present for the induction of anesthesia with a variety of disease states that can increase or lower CO. If initial propofol kinetics are CO-dependent, there are implications for the choice of dose regimen of propofol and the risk of cardiovascular side effects in such patients. Furthermore, CO-dependent kinetics may provide the opportunity of altering the initial concentrations of propofol by transiently altering the CO with another drug, and this may also have therapeutic implications.
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Methods |
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All experimental protocols were approved by our animal ethics committee. Female Merino sheep of similar ages and body mass (approximately 50 kg) were used, and they were instrumented under general anesthesia as described previously (14). Chronic instrumentation included catheters in the carotid artery (for sampling of arterial blood and direct measurement of mean arterial blood pressure [MAP]), in the inferior vena cava outside the right atrium (for drug administration), and in the pulmonary artery (for sampling afferent blood to the lungs and thermodilution measurement of CO). For the second study, the sheep were also prepared with sagittal sinus blood sampling catheters to collect effluent blood from the brain and ultrasonic Doppler flow probes on the sagittal sinus to measure an index of cerebral blood flow, as described previously (14). After preparation, the sheep were allowed to recover from anesthesia and were housed in metabolic crates. The catheters were continuously flushed with heparinized saline as previously described (14).
Study 1: CO Altered by Hypo- and Hypercapnia Under Halothane Anesthesia
We studied six sheep prepared as described above. They were later reanesthetised (IV thiopental 1000 mg and halothane 2%–3%), tracheally intubated, and mechanically ventilated. MAP was monitored throughout the anesthetic procedure and was maintained near the baseline value with infusions of isotonic sodium chloride solution if necessary. After waiting 1.5 h for the induction drug to clear, three steady-state levels of CO (nominally low, medium, and high) were achieved consecutively and in random order by altering arterial carbon dioxide tension via changes in the rate of ventilation. The low state was achieved by hyperventilating the animal to an ETCO2 (Model OIR 7101; Nihon Kohden Corporation, Tokyo, Japan) of approximately 25 mm Hg. The high state was achieved by hypoventilating the animal until the ETCO2 was >70 mm Hg. The medium state was achieved by selecting a ventilation rate that gave an ETCO2 of approximately 40 mm Hg.
Once the ETCO2 for each state had stabilized, CO was measured at least three times by consecutive injections of 10 mL of ice cold 0.9% saline, with integration of the pulmonary artery temperature change and CO calculation using a CO computer. The CO was taken as the mean of these measurements. Shortly thereafter, propofol was infused IV (100 mg over 2 min). Pulmonary arterial blood (0.5 mL) was sampled 0.5, 1, 1.5, 2, 3, 4, and 5 min after the start of the infusion, and arterial blood (0.5 mL) was sampled at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, 6, 8, and 10 min. Sufficient time (1.5 h) was allowed between the propofol infusions at each CO state for the previous dose to be cleared from the blood. The propofol concentrations in blood were determined using a previously described high-performance liquid chromatography method (14).
For each CO state in each sheep, the AUC of the arterial and pulmonary artery concentration curves to 4 min (AUC0–4) was determined using the trapezoidal rule, and their inverse was plotted against the mean COs measured immediately before the infusion to produce inverse plots. The peak pulmonary arterial and systemic arterial concentrations achieved during the infusion were also recorded, and their inverse was plotted against CO. Linear regression was used to determine the slope, intercept, and R2 values of these plots using a statistical program. The P value for the hypothesis that the slope of the regression was significantly different from zero (i.e., a significant effect of CO) was also determined using this program. In addition, the 95% confidence intervals of the regressions were determined using a plotting program (SigmaPlot for Windows 1.0; Jandel Scientific, San Francisco, CA).
Study 2: Cardiac Output Altered by Metaraminol Infusion
Five sheep were instrumented under anesthesia as described above, but they were studied in a conscious state at least 1 wk after surgery. Control and metaraminol experiments were performed in each sheep in random order and separated by at least 2 days. For the control experiments, 100 mg of propofol was infused IV over 2 min, and blood samples were taken from the arterial catheter at the times used for the previous study. Sagittal sinus blood samples were taken at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 10 min. CO was measured using the thermodilution method described above, immediately before and 2, 5, 10, and 20 min after the start of the propofol infusion, and an index of cerebral blood flow was recorded continuously.
The metaraminol experiments differed from the control experiments in that an IV infusion of metaraminol (Merck Sharp and Dohme, Granville, NSW, Australia) was commenced at a rate of 0.5 mg/min approximately 3 min before the start of the propofol infusion and was stopped at the end of the propofol infusion. CO was measured immediately before the metaraminol infusion; immediately before the propofol infusion; and 2, 5, 10, and 20 min after the start of the propofol infusion. The blood samples were later analyzed for propofol as described above.
For each experiment, the arterial AUC0–4 and peak arterial concentrations were calculated, their inverse was plotted against CO, and linear regression was performed, as described for the previous study. The time courses of the brain concentrations of propofol were calculated from the arterial-sagittal sinus concentration gradient and cerebral blood flow using mass balance principles as described previously (14). The AUC of the arterial and brain concentrations for the 10-min period (AUC0–10) were determined using the trapezoidal rule. A two-tailed paired t-test was performed to test for changes in AUC0–10 in metaraminol studies compared with control.
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Results |
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As previously reported, changes in ventilatory rate had a profound effect on CO (15). The mean preinfusion CO (and their lower and upper 95% confidence intervals) for the six sheep in the low, medium, and high CO states were 3.52 (2.96–4.06), 5.21 (4.58–5.83), and 6.38 (5.21–7.54) L/min, which were statistically different among states by comparison of the 95% confidence intervals (16).
For each CO state, the mean pulmonary artery concentrations increased progressively during the infusion and reached a peak value at the end of the infusion (Fig. 2). In two sheep, the pulmonary artery catheter stopped sampling so that the 5-min sample could not be collected, and it was stopped in one sheep so that the 4- and 5-min samples were missed. As the concentration peak had declined substantially by 4 min (Fig. 2), AUC0–4 was used for the analysis, and the one sheep with a missing sample at 4 min was excluded from the analysis. The inverse of AUC0–4 is plotted against the CO in Figure 3, together with the linear regression and a line showing the theoretical maximal slope (1/Dose) predicted by Equation 1. The R2 value, slope, intercept, and P value of the regression were 0.57, 0.0049, 0.0095, and 0.0005, respectively; the latter therefore showed a significant effect of CO. The slope was 49% of the theoretical maximal slope (1/Dose = 0.01) if the observed concentrations were entirely due to first-pass effects. The inverses of the peak pulmonary artery concentrations are also plotted against the CO in Figure 3. The R2 value, slope, intercept, and P value of the regression fit were 0.66, 0.0150, 0.0152, and <0.0001, respectively; the latter therefore showed a significant effect of CO.
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As for the pulmonary artery concentrations, the systemic arterial concentrations progressively increased during the infusion (Fig. 2). The inverses of AUC0–4 showed linear relationships with CO; the R2 value, slope, intercept, and P value of the regression fit were 0.68, 0.0052, 0.0144, and <0.0001, respectively; the latter therefore showed a significant effect of CO. The slope was 52% of the theoretical maximal slope (1/Dose = 0.01) if the observed concentrations were entirely due to first-pass effects. For the peak arterial concentrations, the corresponding values were 0.71, 0.0110, 0.0328, and <0.0001, respectively; the latter reflects a significant effect of CO. Thus, the CO dependence was not greatly altered by the passage of propofol through the lungs.
By comparing the pulmonary artery and systemic arterial concentrations, it is possible to make some inferences about the lung kinetics of propofol. First, the fact that the shape of the concentration curves from both sites is similar suggest that propofol has a relatively small distribution volume in the lungs, consistent with previous findings (3). Second, by comparing the AUC at each site, the mean percentage of propofol retained in the lung for all CO states in Study 1 was 16.4% (10.8–22.0). There is circumstantial evidence that this retained drug is due to metabolism, rather than deep distribution in the lungs (3).
In the second study, it was not possible to measure CO before the propofol infusion in one metaraminol experiment in one sheep, and, in another, the COs were uncharacteristically low, and the method of measurement was presumed to be at fault. The inverses of the peak arterial concentrations and AUC0–4 are shown plotted against CO in Figure 3 together with the data from Study 1. The linear relationship with CO was apparent but less pronounced due to more variable data and less measurements. For the peak arterial concentrations, the R2 value, slope, intercept, and P value of the fit were 0.52, 0.0084, 0.0649, and 0.0436, respectively; the latter again indicated a significant effect of CO. For the arterial AUC0–4, the corresponding values were 0.46, 0.0066, 0.0316, and 0.0437, the latter also showing a significant effect of CO.
Both the peak concentrations and AUC were lower (higher inverse), suggesting greater lung retention of propofol in these studies. A comparison of the mean arterial AUC for this study with the mean pulmonary artery AUC for the high CO state in Study 1 can be used to estimate the retention of propofol in the lungs as approximately 48%. The higher retention in Study 2 may be consistent with the fact that the halothane anesthesia used in Study 1 suppressed the lung metabolism of propofol compared with the conscious experiments of Study 2. These findings are in agreement with the work of others (17). A dose of 100 mg is in the linear metabolism range in sheep (14).
For the sheep in the Study 2, the mean CO immediately before the propofol infusion in the control experiments was 7.27 (5.20–9.35) L/min, and this was statistically lower in the experiments when metaraminol was infused concurrently: 5.14 (3.73–6.54) L/min (Fig. 4) by comparison of 95% confidence intervals (16). This lowered CO state was present only during the 2 min of the propofol infusion—immediately after the infusion when both drugs were ceased the CO rapidly increased to values above the preinfusion baseline (Fig. 4). There were no effects of propofol alone on CO in the control experiments, whereas cerebral blood flow showed a reduction consistent with previous reports (14) and a lower cerebral metabolic rate (Fig. 4). There were only minor differences in the time course of cerebral blood flow between the control and metaraminol studies (Fig. 4).
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) and without (
) a concurrent metaraminol infusion when 100 mg of propofol was infused over 2 min for Study 2. Metaraminol produced a lower cardiac output at the time of the propofol infusion. Bottom, The corresponding data for cerebral blood flow (CBF) expressed as a percentage of baseline calculated from the output of the sagittal sinus Doppler probe. * Statistically significant difference between the metaraminol and control experiments by analysis of the 95% confidence intervals at the time shown (The average (±SEM) MAP was also unaffected by propofol throughout the control experiments (range 102–111 mm Hg) but, as expected, increased progressively during the metaraminol infusion in the metaraminol experiments: 114 ± 5 mm Hg before metaraminol, 143* ± 6 mm Hg before propofol, 148* ± 13 mm Hg 2 min after propofol, 135* ± 13 mm Hg at 4 min, 129 ± 6 mm Hg at 10 min, and 113 ± 5 mm Hg at 20 min (values marked with an asterisk were statistically significantly greater than baseline by analysis of 95% confidence intervals) (16). The lowered CO measured in the metaraminol experiments is therefore consistent with a reflex response to vasoconstriction.
The time courses of the arterial concentrations achieved for the control and metaraminol experiments are shown in Figure 5. The arterial concentrations were increased consistent with the lower CO during the infusion, in agreement with the results of Study 1. The mean peak concentrations at the end of the infusion for the control and metaraminol experiments were 6.3 (3.5–9.3) and 10.2 (7.5–12.9) mg/L, respectively. The AUC0–10 for the arterial and brain concentrations are summarized for each sheep in Table 1. The net increase of these AUC were 143% and 161% of control, respectively. The P values of a two-tailed paired t-test of these data were 0.015 and 0.072 for arterial blood and the brain, respectively. The former is statistically significant at the 95% confidence level and supports the hypothesis that lowering CO increased both peak concentration and initial AUC at this site. Thus, the infusion of a drug that altered CO affected the initial concentrations of another drug. The change in the brain AUC was not statistically significant at the 95% confidence level but showed a consistent increase in each study, in agreement with the trend seen with the arterial data.
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Discussion |
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The simple analysis presented in the Introduction and shown in Figure 1 is useful for considering the circumstances in which the arterial concentrations of a drug may be significantly influenced by the first-pass concentrations. Drug recirculation is often considered to occur quickly based on experience with intravascular markers. For many drugs with relatively large distribution volumes, and for individuals with no arteriovenous shunts, this is unlikely to be the case with mean transit times of drugs even through highly perfused organs of the order of minutes rather than seconds.
In addition, CO is the sum of the blood flows to all organ systems arranged in parallel in the circulation (this excludes the lungs), and different methods for altering CO may alter the relative distribution of the CO to these organs. For example, the lowered CO in Study 2 resulted in flow to the brain being relatively unchanged compared with control, whereas flow to other organs (e.g., skeletal muscle and gut) may have decreased, thus increasing the relative distribution to the CO to the brain and increasing the initial cerebral uptake of propofol. Rigorous analysis therefore requires consideration of the effect of both CO and target organ blood flow (3,18).
The indicator dilution effect (Equation 1) is not inherent in traditional compartmental pharmacokinetic models, in which an IV injected drug is considered to be added to a hypothetical volume (the initial distribution volume) rather than to a stream of flowing blood. A major limitation of this assumption is that the physiological interpretation of this volume is ambiguous (e.g., whether it is represented by arterial or venous blood), and it does not account for the rate of circulation of the blood (the CO). A number of physiologically based (1,2) and recirculatory stochastic models (5,6) have incorporated descriptions of recirculation that avoid this limitation, and analyses of these models often conclude that the kinetics of a drug are dependent on the CO when its influence is considered. Physiologically based models will not produce a CO effect of the magnitude described in this article if the drug is assumed to be added to the entire venous blood volume rather than the smaller volume between the injection site and the pulmonary artery. This effect is minimized, and initial mixing can be approximated, by assuming that the drug is added directly to the lung compartment of a physiological model (2,19). In agreement with a previous model of propofol kinetics in sheep (3), these models also found a similar degree of CO dependence in initial kinetics.
Few experimental studies have examined the influence of CO on drug kinetics. A study in rats (20) showed a good correlation between the nitroglycerin concentrations achieved during an IV infusion and CO. The dose requirements of thiopentone (8) and postinfusion kinetics of alfentanil (7) were shown to be correlated with CO in humans. When halothane was used to decrease CO in dogs (9), the AUCs of a number of indicators in the first minutes after bolus injection were inversely related to the CO in a manner consistent with a significant contribution of first-pass concentrations. The kinetics of sorbital were CO-dependent when analyzed using a stochastic recirculatory model (6).
The present study is the first to examine in vivo the significance of altered CO on the initial concentrations of propofol. The clinical implications of these data depend on the extent that such a CO effect can be expected to occur in humans. As previously discussed, the first-pass effect would be most significant for high-clearance drugs for which the initial concentrations and effects are clinically important (e.g., IV anesthetics). The most important implication for propofol arises from the inverse nature of the relationship between peak concentration and CO. Thus, particularly high concentrations (and greater adverse hemodynamic effects) (21) could be expected if a normal dose of propofol was injected into patients with a low CO. This is consistent with the experience of most anesthesiologists, in that critically ill patients with low COs usually require very small doses of propofol. However, other factors undoubtedly contribute to this effect.
The observation that a drug that alters CO can affect the initial kinetics of propofol also has interesting implications and agrees with previous findings regarding the administration of dexmedetomidine with thiopental (22). It could be speculated that a reduction in CO caused by the coadministration of drugs such as midazolam and fentanyl (23,24) to potentially anxious patients may be an additional pharmacokinetically based mechanism by which these drugs reduce the induction dose of propofol.
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Acknowledgments |
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Supported by the National Health and Medical Research Council of Australia, the Royal Adelaide Hospital-Research Review Committee and Special Purposes Fund, and the Ramaciotti Foundation.
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J. Morris, M. Acheson, M. Reeves, and P. S. Myles Effect of clonidine pre-medication on propofol requirements during lower extremity vascular surgery: a randomized controlled trial Br. J. Anaesth., August 1, 2005; 95(2): 183 - 188. [Abstract] [Full Text] [PDF]
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Y. Oda, K. Nishikawa, I. Hase, and A. Asada The Short-Acting {beta}1-Adrenoceptor Antagonists Esmolol and Landiolol Suppress the Bispectral Index Response to Tracheal Intubation During Sevoflurane Anesthesia Anesth. Analg., March 1, 2005; 100(3): 733 - 737. [Abstract] [Full Text] [PDF]
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 M. J. Avram, T. C. Krejcie, T. K. Henthorn, and C. U. Niemann {beta}-Adrenergic Blockade Affects Initial Drug Distribution Due to Decreased Cardiac Output and Altered Blood Flow Distribution J. Pharmacol. Exp. Ther., November 1, 2004; 311(2): 617 - 624. [Abstract] [Full Text] [PDF]
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J. R. Sneyd Recent advances in intravenous anaesthesia Br. J. Anaesth., November 1, 2004; 93(5): 725 - 736. [Abstract] [Full Text] [PDF]
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R. N. Upton The two-compartment recirculatory pharmacokinetic model--an introduction to recirculatory pharmacokinetic concepts Br. J. Anaesth., April 1, 2004; 92(4): 475 - 484. [Abstract] [Full Text] [PDF]
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G. L. Ludbrook and R. N. Upton Pharmacokinetic Drug Interaction Between Propofol and Remifentanil? Anesth. Analg., September 1, 2003; 97(3): 924 - 925. [Full Text] [PDF]
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K. B. Johnson, T. D. Egan, J. Layman, S. E. Kern, J. L. White, and S. W. McJames The Influence of Hemorrhagic Shock on Etomidate: A Pharmacokinetic and Pharmacodynamic Analysis Anesth. Analg., May 1, 2003; 96(5): 1360 - 1368. [Abstract] [Full Text] [PDF]
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K. S. Kim, M. A. Cheong, J. W. Jeon, J. H. Lee, and J. C. Shim The Dose Effect of Ephedrine on the Onset Time of Vecuronium Anesth. Analg., April 1, 2003; 96(4): 1042 - 1046. [Abstract] [Full Text] [PDF]
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M. J. Avram, T. C. Krejcie, and T. K. Henthorn The Concordance of Early Antipyrine and Thiopental Distribution Kinetics J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 594 - 600. [Abstract] [Full Text] [PDF]
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T. C. Krejcie, Z. Wang, and M. J. Avram Drug-Induced Hemodynamic Perturbations Alter the Disposition of Markers of Blood Volume, Extracellular Fluid, and Total Body Water J. Pharmacol. Exp. Ther., March 1, 2001; 296(3): 922 - 930. [Abstract] [Full Text]
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Y. U. Adachi, K. Watanabe, H. Higuchi, and T. Satoh The Determinants of Propofol Induction of Anesthesia Dose Anesth. Analg., March 1, 2001; 92(3): 656 - 661. [Abstract] [Full Text] [PDF]
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T. C. Krejcie and M. J. Avram What Determines Anesthetic Induction Dose? It's the Front-End Kinetics, Doctor! Anesth. Analg., September 1, 1999; 89(3): 541 - 541. [Full Text] [PDF]
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