The influence of infusion rate on the induction dose-response relation has not been investigated over a wide range of infusion rates. In this study, the authors defined the effect of different propofol infusion rates on the times and doses necessary to reach clinical induction of anesthesia.
The subjects of the study were 250 patients classified as American Society of Anesthesiologists physical status I or II aged 25-55 yr. For induction with undiluted propofol, 180 patients were allocated randomly to one of two groups of 90 patients each (A and B). Each group was further divided into nine subgroups (10 patients each) that were administered propofol infusion at rates of 10, 15, 20, 30, 40, 60, 100, 200, and 300 mg/kg-1/h-1. The remaining 70 patients (group C) were allocated randomly into seven subgroups (10 patients each), and these groups were induced with diluted propofol (0.5 mg/ ml) at the rates of 10, 15, 30, 60, 100, 200, and 300 mg/kg-1/ h-1. Group B was given crystalloid at the same infusion rates as group C via a catheter in the opposite arm. Induction time, induction dose, plasma arterial propofol concentration at loss of consciousness, and percentage decrease of systolic blood pressure were measured. A previously reported three-compartment model with an effect-site rate constant for propofol of 0.456/min was used to predict the induction time and dose at each infusion rate.
The differences between predicted induction time and dose and the observed time and dose could be explained by factoring in the lag time from infusion site to central compartment (lag time circulation) and the amount of propofol in transit during this time (residual dose circulation). Residual dose circulation and lag time circulation correlated with infusion time from 20 to 60 s for undiluted and from 0 to 40 s for diluted propofol. At the infusion rates greater than 80 mg/kg-1/h-1, rapid circulation because of incomplete mixing in the central compartment decreased the excess induction time and dose. The use of diluted propofol significantly attenuated the decrease in systolic blood pressure provoked by the residual dose circulation.
Induction dose and time are dependent on infusion rate in a complex manner, and residual dose circulation was a factor in overdose and hemodynamic depression. Hypotension during induction was attenuated by diluted propofol.
THE importance of injecting propofol slowly to avoid an overdose and to minimize cardiorespiratory depression is widely accepted. 1–3However, previous reports show substantial variability in the relations among infusion rate, induction dose, and induction time. Many researchers have reported that a slower rate of propofol administration for induction of anesthesia results in smaller dose requirements and that the time necessary for induction is significantly longer at slower infusion rates. 3,4This seems to be a straightforward simple correlation; however, it is not so simple. The relations among rate of drug administration, induction time, and dose requirement pose interesting questions that merit further consideration because of the variety of possible relations among infusion rate, induction time, and dose. 5–7These relations have not been investigated systematically using a wide range of infusion rates.
In traditional pharmacokinetic models, an intravenously administered drug is assumed to be injected into the central compartment rather than into a stream of flowing blood. This becomes a major limitation of assumptions about the physiologic effect of a drug, especially at a high infusion rate. With administering a drug that is carried through the circulatory system to the site of drug effect, a certain amount of drug is contained in the circulation from the site of administration to the central compartment. The lag time from infusion site to central compartment (lag timecirculation) and the amount of this drug in circulation (residual dosecirculation), which is correlated with lag timecirculation, are dependent on the infusion rate and dilution of the drug.
In addition to the lag timecirculation, there is another lag time from the central compartment to effect site that is defined as the time constant of the effect-site rate constant (keO) and the dose in the central compartment at loss of consciousness (residual dosecentral) is dependent on the infusion rate of the drug.
If propofol administration is titrated with a high continuous propofol infusion rate, the anesthesiologist may administer a larger dose than is necessary to achieve loss of consciousness, and such large doses may cause a decrease in systemic arterial blood pressure. However, the relation between rate of infusion and induction dose described by previous reports is incomplete because of the small range of infusion rates used and the lack of consideration of all residual doses.
The current study was designed (1) to determine the relation between infusion rate, induction time, and induction dose using a wide range of propofol infusion rates from 10–300 mg · kg−1· h−1; (2) to determine whether the use of diluted propofol lessens the residual dosecirculation; (3) to compare our results with a previously published pharmacokinetic and pharmacodynamic model; and (4) to investigate the hemodynamic responses to these various infusion states.
Materials and Methods
Written, informed consent was obtained from each patient after explanation of the study, which was approved by the District Ethics Committee of the Hamamatsu University Hospital. The subjects selected for this study were unpremedicated patients classified as American Society of Anesthesiologists physical status I or II, aged 25–55 yr, who were scheduled for elective surgery. Exclusion criteria included a history of cardiac, pulmonary, liver, or renal disease and the presence of significant obesity (body mass index > 26). At arrival of the unpremedicated patient in the operating room, an 18-gauge cannula was inserted into a large antecubital vein during local anesthesia. Lactated Ringer’s solution was infused (3 ml · kg−1· h−1) until the start of propofol infusion for anesthesia induction. During baseline recording, oxygen was administered with a face mask. Anesthesia was induced using a previously assigned propofol infusion rate until loss of verbal contact with the patient. The patients were asked to open their eyes or to otherwise indicate that they were still conscious. If no response to this stimulus occurred, the patients were stimulated by gently rubbing and tapping their shoulders. Loss of consciousness was defined as no response to these stimuli. In all patients, responses to stimuli were assessed every 20, 10, 5, and 2.5 s at the infusion rates from 10–15, from 20–30, from 40–100, and from 200–300 mg · kg−1· h−1, respectively, by the same attending anesthesiologist and the same assistant resident anesthesiologist, who were both blind to the assigned infusion rate or infused propofol concentration. Both anesthesiologists were completely familiar with the strict definition of response. The induction time was defined as the time from the start of propofol infusion to loss of consciousness, and the induction dose was defined as the amount of propofol administered before loss of consciousness.
Induction with Undiluted Propofol (10 mg/ml; Group A)
After 5 min preoxygenation, propofol was administered by infusion pumps through a three-way tap placed directly into the venous cannula. During propofol infusion, lactated Ringer’s solution was discontinued. Ninety patients were assigned randomly to nine study groups (10 patients/group) to receive infusion of propofol at one of the following rates: 10, 15, 20, 30, 40, 60, 100, 200, or 300 mg · kg−1· h−1(table 1). Infusion was controlled by conventional syringe infusion pump (Graseby 3500; Graseby Medical, Colonial Way, Watford, Herts, UK), with rates of 60 mg · kg−1· h−1or more necessitating several infusion pumps at once because of the infusion-rate limitation of a single pump.
Induction with Undiluted Propofol Accompanied by Crystalloid Solution Infusion in the Opposite Hand (Group B)
Ninety patients were assigned randomly to one of nine study groups of different undiluted propofol infusion rates: 10, 15, 20, 30, 40, 60, 100, 200, or 300 mg · kg−1· h−1. Propofol administration followed the same procedures as described for group A. A second intravenous infusion catheter was placed in the opposite hand for lactated Ringer’s solution infusion at rates of 20, 30, 40, 60, 80, 120, 200, 400, or 300 ml · kg−1· h−1at the same time as each respective propofol infusion (table 2). For infusion rates less than 40 ml · kg−1· h−1, lactated Ringer’s solution was infused with Graseby syringe infusion pumps. At the other infusion rates, it was infused manually, and the infusion volume was checked every second. After loss of consciousness, the infusion rate was adjusted again to 3 ml · kg−1· h−1.
Induction with Diluted Propofol (Group C)
Seventy patients were assigned randomly to one of seven groups of different diluted propofol infusion rates: 10, 15, 30, 60, 100, 200, or 300 mg · kg−1· h−1(table 3). Diluted propofol at 0.5 mg/ml was used for induction except for the infusion rate of 300 mg · kg−1· h−1, for which diluted propofol at 1.0 mg/ml was used because of the technical limitations of infusion speed. Propofol diluted 20 times with lactated Ringer’s solution was prepared just before anesthesia induction. After 5 min preoxygenation, propofol was infused at the assigned rates through the three-way tap placed directly into the venous cannula. For the infusion rates less than 15 mg · kg−1· h−1, diluted propofol was infused with Graseby syringe infusion pumps. For the other infusion rates, diluted propofol was infused manually as described previously.
Pain or discomfort at the site of injection during or after propofol administration was recorded and graded by the attending anesthesiologist as mild, moderate, or severe, according to patient facial expressions, arm movements, or reports of pain. Incidents of spontaneous movement and vocalization during induction were recorded. End-tidal carbon dioxide measurement was used to detect any incidence of apnea lasting more than 30 s. Spontaneous respirations were assisted manually if necessary. Heart rate, electrocardiographic data, end-tidal carbon dioxide, oxyhemoglobin saturation, and noninvasive blood pressure (1-min interval; CBM7000; Nihon Colin, Komaki, Japan) were monitored continuously throughout this study.
Immediately after loss of consciousness, infusion of undiluted propofol (10 mg/ml) was commenced at 4 mg · kg−1· h−1, and hemodynamic change was recorded for 20 min. Then, intubation was facilitated by fentanyl, 0.1 or 0.2 mg, and vecuronium, 0.1 mg/kg.
Cardiovascular recordings were made for 5 min at the commencement of monitoring as a baseline measurement. The minimum value of systolic blood pressure (SBP) during the 20 min after loss of consciousness and the heart rate at the minimum SBP were designated as the postinduction values. If hypotension (< 75 mmHg, or > 40% SBP decrease) persisted for 2 or 3 min, patient blood pressure was restored by ephedrine.
Although propofol was infused as a function of real body weight, the relation among induction dose, induction time, SBP decrease, propofol plasma concentration, and propofol infusion rate was investigated as a function of lean body mass (LBM). LBM was determined from height (cm) and weight (kg) using gender-specific formulas. 8
Women: LBM = 1.07 × weight − 148 ×
Men: LBM = 1.10 × weight −128 × (weight/height)2
At a 24-h postoperative examination, each patient was asked whether he or she recalled any event occurring after loss of consciousness. At that time, the injection site was evaluated for possible phlebitis, irritation, or thrombosis.
A femoral arterial blood sample (3 ml) was taken from each patient for analysis of plasma propofol concentration at unresponsiveness to verbal and tactile stimuli. The blood samples were immediately placed on ice, after which the plasma was separated and frozen at −70°C until it was assayed. 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). The lower limit of detection was 32 ng/ml.
Simulations of Infusion Rate versus Propofol Induction Dose and Induction Time
To simulate the blood concentration histories of zero-order infusions/LBM at rates from 10–450 mg · kg−1· h−1, previous pharmacokinetic parameters for a 42-yr-old, 57-kg, 160-cm man reported by Schnider et al. 9were used. The keOfor propofol equilibration of 0.456/min−1was used to link the effect with the central compartment propofol concentrations. 10Effect-site concentration at loss of consciousness (CeLOS) was adjusted to 3.49 μg/ml as the simulated induction dose derived from the findings of Schnider et al. 9findings became equal to our mean induction dose of group A10(table 1). The infusion rate used in our group A10was the same as that in the Schnider et al. 9study. 9The pharmacokinetic parameters of Schnider et al. 9were derived from the data of an extremely low infusion rate, from 1.5–12 mg · kg−1· h−1, at which lag timecirculationand residual dosecirculationwere negligible because lag timecirculationis extremely small compared with induction time. Induction dose and time to reach the normalized effect-site concentration of loss of consciousness (3.49 μg/ml) were calculated at constant infusion rates/LBM from 10–450 mg · kg−1· h−1at each infusion rate in increments of 2.5 (from 10–50 mg · kg−1· h−1) or 10 mg · kg−1· h−1(from 50–450 mg · kg−1· h−1). If lag timecirculationwas 0, 10, 20, 40, or 60 s, induction dose was calculated by adding residual dosecirculationto the value predicted using the pharmacokinetic parameters of Schnider et al. 9
All data are presented as the mean ± SD. The data for quality of induction in each group were compared with Kruskal–Wallis tests. To compare groups A, B, and C, except for infusion volumes, one-way analysis of variance was used. Post hoc analysis using the Bonferroni correction of the Student t test would have been performed if differences had been found. P < 0.05 was considered statistically significant.
Among the 250 patients, 10 in each infusion subgroup of groups A, B, and C, there were no statistically significant differences between the groups in gender ratio, age, height, weight, or LBM (tables 1–3). In all groups, anesthesia could be induced within 15 min with the predetermined propofol infusion rates, and no patients needed an additional propofol bolus infusion because of unsuccessful induction. The quality of anesthesia induction with propofol in all groups is summarized in table 4. Apnea occurred far more often at the faster administration rates than at the slower ones.
There was no excitatory movement. Injection pain was 5–30% in each group. In the diluted propofol group, higher propofol injection rates tended to provoke increases in the intensity of pain. Vocalization, meaning spontaneous speech, was significantly more frequent at lower infusion rates than at higher ones in groups receiving undiluted and diluted propofol both. At 24-h postoperative examinations, no patients showed complications such as persistent pain, redness, swelling, thrombophlebitis, and memory of awareness during induction. Three patients, two from group A and one from group B, were administered ephedrine because of hypotension. We recorded the lowest SBP before injection of ephedrine in these patients. In three patients from group A, blood samples could not be obtained within 10 s after loss of consciousness.
Various rates of crystalloid solution infusion in the opposite hand had no significant effect on induction time, induction dose, plasma propofol concentration at loss of consciousness, or percentage decrease in SBP (tables 1 and 3).
The induction time showed an initial steep decrease; however, it became fairly flat at infusion rates greater than 100 mg · kg−1· h−1(fig. 1). At all infusion rates, observed induction time necessary with undiluted propofol was an average of 21.9 s greater than that necessary with diluted propofol. In undiluted propofol, simulated induction time calculated with previously reported pharmacokinetic and pharmacodynamic parameters 9,10was underestimated compared with the observed induction time (fig. 1). The observed mean induction times at infusion rates greater than 100 mg · kg−1· h−1clearly were relevant to the simulated induction time with a 20-s lag timecirculation(fig. 1). In diluted propofol, the observed times at rates more than 100 mg · kg−1· h−1were relevant to the predicted line with a 0-s lag timecirculation(fig. 1).
The relation between induction dose and infusion rate was not simple. In the simulation this relation clearly was concave when plotted (fig. 2). However, plotting the observed relation between induction dose and infusion rate did not produce a clear concave line. At infusion rates less than 80 mg · kg−1· h−1for undiluted propofol, the actual observed dose for induction was similar to the predicted dose combined with an additional residual dosecirculationthat corresponds with a 60-s lag timecirculation. At the infusion rates greater than 80 mg · kg−1· h−1, the observed dose was similar to the predicted dose combined with an additional residual dosecirculationthat corresponds with 20 s of lag timecirculation(fig. 2). For diluted propofol, the observed dose was similar to the predicted dose combined with an additional residual dosecirculationcorresponding to 40 s of lag timecirculationat infusion rates less than 80 mg · kg−1· h−1. At infusion rates greater than 80 mg · kg−1· h−1, the observed dose was similar to the predicted dose (fig. 2). In all infusion rates, the induction doses with undiluted propofol were greater than those with diluted propofol, and the difference corresponded to the residual dosecirculationfor approximately 20–30 s at each infusion rate (fig. 2).
The plasma propofol concentration at loss of consciousness increased with propofol infusion rate in all groups (fig. 3;tables 1–3). Although at the infusion rates less than 40 mg · kg−1· h−1the plasma concentrations for both undiluted and diluted propofol were similar, the concentrations for undiluted propofol were significantly higher than those for diluted propofol at higher infusion rates.
Systolic blood pressure did not change significantly at infusion rates less than approximately 80 mg · kg−1· h−1of undiluted and diluted propofol. At infusion rates greater than 80 mg · kg−1· h−1, SBP decreased significantly in the undiluted propofol groups (fig. 4;tables 1 and 2). In the diluted propofol groups, decreases in SBP were less marked, even at higher infusion rates (fig. 4;table 3).
We evaluated the induction state from extremely low rates to extremely high rates of undiluted or diluted propofol infusion, which encompassed a much greater range than reported previously. 2,3,5,11–13Combined pharmacokinetic–pharmacodynamic models are useful for determining the influence of administration, disposition, and effect. 6,9,11,14These models can be used to predict the time course and intensity of drug effect if a drug is infused at various rates. When we acquired curves of simulated infusion rate versus induction dose, the effect-site concentration at loss of consciousness in the Schnider et al. 9model was adjusted as the predicted induction dose became equal to our observed induction dose at the infusion rate of 10 mg · kg−1· h−1. This normalization is reasonable, because the Schnider et al. 9pharmacokinetic parameters used in the simulation were derived from data of a propofol infusion rate from 1.5–12 mg · kg−1· h−1. The simulated infusion rate versus induction dose indicates a concave curve. The simulation could predict propofol induction dose generally during the extreme condition of a 30-fold range of infusion rates. However, there were systematic differences between our observed induction dose and the dose predicted by this model even if we normalized this model to our data.
Previous descriptions of the relation between rate of infusion and induction dose have been incomplete because not all necessary components were evaluated. 3,4The relation between induction dose and infusion rate can be explained with four primary factors.
First is the amount of propofol removed from the central compartment, with clearance that depends on the concentration in the central compartment. The clearance from the central compartment by metabolism and distribution is approximately 4.0–5.5 l/min. 9,15Second is the residual dosecentral. Although the plasma concentration peaks almost instantly, additional time is necessary for the drug concentration in the brain to rise and induce unconsciousness. The time lag is defined as time constant of keOof the effect site. Third is residual dosecirculationthat is correlated with lag timecirculation. This has not been investigated precisely. Fourth is rapid circulation, which is provoked by incomplete drug mixing in the central compartment. These factors act on the relation between induction dose and infusion rate in a complex manner.
Relations among infusion rate and induction dose, metabolic clearance dose, and residual dosecentralare simulated in figure 5based on pharmacokinetic and pharmacodynamic parameters of Schnider et al. 9,10. At the infusion rate of 10 mg · kg−1· h−1, half the induction dose was attributed to metabolic clearance dose, and only 4.6% was attributed to residual dosecentral. At the infusion rate of 450 mg · kg−1· h−1, only 7.2% of the induction dose was attributed to metabolic clearance dose, and 82% was attributed to the residual dosecentral.
The relations among infusion rate and predicted induction dose, induction time, and propofol concentration of the central compartment at loss of consciousness at various keOs of 0.2, 0.3, and 0.456/min−1are shown in figure 6. With increasing keO, propofol concentration of effect site equilibrated more rapidly with the concentration in the central compartment. Because of the lag time between central compartment and effect site, concentration in the central compartment increases as infusion rate increases. At higher infusion rates, the central concentration increases more rapidly than does the effect-site concentration, and central compartment concentration at loss of consciousness reaches a relatively high value. Consequently, residual dosecentralis larger, which results in quicker onset and increased duration of drug effect.
The concave outline of the infusion rate–induction dose relation can be explained generally by metabolic clearance dose and residual dosecentral. However, the predicted induction dose was different from the observed dose, although it was normalized at an extremely low infusion rate (fig. 2). These observations cannot be explained by clearance dose or residual dosecentral. Our observed induction dose was higher than that predicted at all infusion rates with the exception of the infusion rate used for normalization in undiluted propofol. Furthermore, the difference between predicted and observed induction dose varied depending on infusion rate and dilution of propofol. At infusion rates less than 80 mg · kg−1· h−1, additional residual dosecirculationfor a 60-s lag time was necessary for induction, whereas at infusion rates more than 80 mg · kg−1· h−1, additional residual dosecirculationfor a 20-s lag time was necessary. For diluted propofol, 40 s for less than 80 mg · kg−1· h−1and 0 s for more than 80 mg · kg−1· h−1of additional residual dosecirculationwere necessary (fig. 2).
At all infusion rates, the difference in residual dosecirculationbetween undiluted and diluted propofol can be explained by the difference of lag timecirculationfor approximately 20 s provoked by a 20-fold dilution of propofol. However, the downward change of induction dose at infusion rates greater than 80 mg · kg−1· h−1in undiluted and diluted propofol cannot be explained with residual dosecirculationand has not been reported previously. In addition to the residual doses, rapid circulation resulting from incomplete mixing of the central compartment helps to explain the downward change at higher infusion rates.
The involvement of rapid circulation resulting from incomplete mixing has been ignored in conventional compartment models. However, the mechanisms of this process are well-understood and can be described by indicator dilution principles. Bolus infusion of indocyanine green can be used to define intravascular mixing transients. After central venous administration, there is a finite delay before the first indocyanine green appears at a sampling site. 16Recirculation returns the drug through the central blood circuit to generate an oscillatory peak, which becomes damped on subsequent recirculations. 17Roerig et al. 18demonstrated in humans that indocyanine green concentration in a radial artery started to increase at approximately 15 s and peaked between 19 and 24 s after a bolus injection from a central venous catheter, with a second peak at 40–42 s representing the second circulation. Vecuronium onset time to 95% twitch depression was 21 s less during administration in the right atrium than in a peripheral vein 19; that is, the lag time between peripheral vein and radial artery is from 36 to 45 s. Our lag timecirculationat infusion rates less than 80 mg · kg−1· h−1was 60 s. Actual lag time between infusion site and radial artery may be different from our lag timecirculationfrom infusion site to central compartment. In our model of low infusion rates, especially those less than 60 mg · kg−1· h−1, the actual observed induction dose was quite similar to the predicted dose combined with an additional residual dosecirculationthat corresponds with 60 s of lag timecirculation, which means that the lag timecirculationof undiluted propofol is 60 s. In the same manner, the lag timecirculationof diluted propofol is 40 s.
If we assume that mixing in the central compartment was complete at high and low infusion rates, the predicted effect-site propofol concentrations at various infusion rates are shown in figure 7. The effect-site concentrations were calculated with effective induction dose (effective induction dose = total induction dose − 60 s residual dosecirculationfor undiluted or 40 s residual dosecirculationfor diluted propofol). At infusion rates greater than 60 mg · kg−1· h−1, the effect-site propofol concentration could not attain the concentration for loss of consciousness (3.49 μg/ml) if compartment mixing was completed immediately. At infusion rates greater than 150 mg · kg−1· h−1, the central compartment propofol concentration is zero. These results provide additional evidence that rapid circulation begins to influence the induction with continuous infusion at infusion rates more than 60 mg · kg−1· h−1, and that it becomes a main factor for induction at infusion rates more than 150 mg · kg−1· h−1.
In continuous infusion, initially, arterial propofol concentration increases more rapidly in a condition of incomplete mixing than in one of immediate complete mixing, although both conditions reach the same concentration progressively. The initial accelerative increase of propofol concentration causes a decrease of induction dose at high infusion rates. Our downward variation of residual dosecirculationat infusion rates more than 80 mg · kg−1· h−1may have resulted from the decrease of induction dose provoked by the incomplete mixing.
For various lag timecirculationvalues, simulation of infusion rate versus propofol concentration of central compartment at loss of consciousness is shown in figure 8. At lower infusion rates, predicted concentrations with measured induction doses for undiluted and diluted propofol were similar, and they were consistent with our observed propofol concentrations. However, at infusion rates greater than 80 mg · kg−1· h−1, our observed plasma propofol concentrations were less than half the predicted ones (figs. 3 and 8). The predicted central concentration was obtained by measuring an induction dose that included residual dosecirculation. Blood samples were taken within 10 s after loss of consciousness, when residual dosecirculationhad not yet circulated to the artery side completely, which explains the discrepancy between predicted and measured propofol concentrations.
Upton 20,21demonstrated that the time course of arterial concentration of drug administered in a bolus injection depends on dose rate, cardiac output, and magnitude of lung extraction. Hemodynamic depression occurs after loss of consciousness because t1/2keO(t1/2keO= ln2/keO) of SBP is 2.5 times more than that of the electroencephalographic bispectral index. 22SBP decreased significantly more than 30% from preinduction values at high infusion rates of undiluted propofol in our study (fig. 4;tables 1–3). Cardiac output might decrease and influence induction dose; however, the maximal SBP decrease occurred after loss of consciousness. This suggests that cardiac output did not change significantly before loss of consciousness, and that it did not affect the induction dose and time in our study.
The crystalloid solution used in the dilution of propofol might change cardiac output. However, in our study, the various crystalloid infusion rates of the opposite hand in group B had no significant effects on induction time, induction dose, plasma propofol concentration at loss of consciousness, or percentage decrease in SBP (tables 1 and 3). The maximum crystalloid infusion rate was approximately 0.4 l/min. We suppose this amount of change in cardiac output would not influence the induction time, dose, or SBP depression.
For steady state lung extraction (Elung[%]) of propofol against pulmonary artery concentration, Upton and Ludbrook 23reported that the relation between the inverse of extraction (1/Elung) and the afferent pulmonary artery concentration (Cpa) could be described by the following equation:
1/Elung= 0.007 Cpa+ 0.013
According to this equation, Elungvalues at 6.0 and 22 μg/ml of pulmonary artery concentrations are 18.2 and 6.0%. If the pulmonary artery concentration is close to the arterial concentration, infusion rates in these pulmonary artery concentrations would be approximately 26 and 385 mg · kg−1· h−1, respectively, in our study (tables 1–3). Consequently, doses extracted with the lung are 0.36 mg/kg at a 26-mg · kg−1· h−1infusion rate and 0.3 mg/kg at a 385-mg · kg−1· h−1infusion rate. This suggests that the dose extracted in the lung is almost constant with low and high infusion rates both, although the lung extraction might affect the induction dose.
In summary, we investigated propofol induction doses using a wide range of infusion rates with undiluted and diluted propofol. In addition to the residual dosecentraland lag time between the central compartment and effect site with increasing infusion rates, induction dose and time increased as much as residual dosecirculationand lag timecirculation. However, at infusion rates greater than 80 mg · kg−1· h−1, rapid circulation resulting from incomplete mixing in the central compartment decreased induction dose and time. Overdosing related to residual dosecirculationcould be alleviated with the use of diluted propofol.