Investigation of Effective Anesthesia Induction Doses Using a Wide Range of Infusion Rates with Undiluted and Diluted Propofol

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.

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.

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.

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 ×

(weight/height)²

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.

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 k^eOfor 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 (Ce^LOS) 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 time^circulationand residual dose^circulationwere negligible because lag time^circulationis 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 time^circulationwas 0, 10, 20, 40, or 60 s, induction dose was calculated by adding residual dose^circulationto 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 time^circulation(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 time^circulation(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 dose^circulationthat corresponds with a 60-s lag time^circulation. 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 dose^circulationthat corresponds with 20 s of lag time^circulation(fig. 2). For diluted propofol, the observed dose was similar to the predicted dose combined with an additional residual dose^circulationcorresponding to 40 s of lag time^circulationat 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 dose^circulationfor 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 dose^central. 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 k^eOof the effect site. Third is residual dose^circulationthat is correlated with lag time^circulation. 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 dose^centralare 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 dose^central. 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 dose^central.

The relations among infusion rate and predicted induction dose, induction time, and propofol concentration of the central compartment at loss of consciousness at various k^eOs of 0.2, 0.3, and 0.456/min⁻¹are shown in figure 6. With increasing k^eO, 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 dose^centralis 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 dose^central. 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 dose^central. 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 dose^circulationfor a 60-s lag time was necessary for induction, whereas at infusion rates more than 80 mg · kg⁻¹· h⁻¹, additional residual dose^circulationfor 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 dose^circulationwere necessary (fig. 2).

At all infusion rates, the difference in residual dose^circulationbetween undiluted and diluted propofol can be explained by the difference of lag time^circulationfor 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 dose^circulationand 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 time^circulationat 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 time^circulationfrom 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 dose^circulationthat corresponds with 60 s of lag time^circulation, which means that the lag time^circulationof undiluted propofol is 60 s. In the same manner, the lag time^circulationof 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 dose^circulationfor undiluted or 40 s residual dose^circulationfor 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 dose^circulationat 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 time^circulationvalues, 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 dose^circulation. Blood samples were taken within 10 s after loss of consciousness, when residual dose^circulationhad 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 t^1/2k^eO(t^1/2k^eO= ln2/k^eO) 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 (E^lung[%]) of propofol against pulmonary artery concentration, Upton and Ludbrook 23reported that the relation between the inverse of extraction (1/E^lung) and the afferent pulmonary artery concentration (C^pa) could be described by the following equation:

1/E^lung= 0.007 C^pa+ 0.013

According to this equation, E^lungvalues 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 dose^centraland lag time between the central compartment and effect site with increasing infusion rates, induction dose and time increased as much as residual dose^circulationand lag time^circulation. 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 dose^circulationcould be alleviated with the use of diluted propofol.