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Sevoflurane End-Tidal to Effect-Site Equilibration in Women Determined by Response to Laryngeal Mask Airway Insertion

Kennedy, Ross MB, ChB, PhD*†; McKellow, Margie; French, Richard MB BS; Sleigh, Jamie MB, ChB, MD

doi: 10.1213/ANE.0b013e3182a46d4e
Anesthetic Pharmacology: Research Report

BACKGROUND: End-tidal concentrations (CET) have been used to guide delivery of inhaled anesthetic drugs for many years. Effect-site concentrations (Ceff) are a frequently used guide to therapy with IV drugs and should also be of benefit with inhaled drugs, especially during periods of rapid change. For Ceff to be useful, the appropriate levels required for any given end point, and the delay between central compartment and effect, need to be defined. In this study, we explored these relationships for the effect of response to insertion of the classic laryngeal mask airway (cLMA) and compared the utility of CET and Ceff-guided cLMA insertion.

METHOD: We studied 30 ASA physical status I or II patients in whom induction with sevoflurane alone and use of the cLMA were appropriate. After oxygen administration from a circle system with a total gas flow of 6 L/min, the sevoflurane vaporizer dial was set to 6%. cLMA insertion was attempted at a predetermined Ceff calculated in real time based on measured CET. Target levels were chosen using up-and-down methodology. The initial value was 2.5 vol% with a step size of 0.2 vol%. Subjects showing a gross motor response were responders, and the target was increased for the next subject. Those without such a response were nonresponders, and the target was decreased for the next subject. Data collection continued until after 7 transitions from nonresponder to responder. For each subject, after the first transition, we calculated a Ceff time series from the measured CET time series for 11 t1/2ke0 values between 0.5 and 5.0 minutes. We combined data from 2 studies of equilibrium 50% effective concentration (EC50) for LMA insertion to derive a pooled EC50 of 2.17%. We determined graphically the t1/2ke0 that gave a mean EC50 of 2.17% in our subjects. We constructed receiver operator characteristic curves to compare the utility of CET and Ceff-guided cLMA insertion.

RESULTS: The 30 patients studied were all women, ASA physical status I or II, aged between 22 and 66 years (mean 38). Consciousness was lost after 99.2 (SD 11.1) seconds, and the target for cLMA insertion reached after 256 (57) seconds. The optimum t1/2ke0 was 2.25 minutes (95% confidence interval, 2.0–2.5 minutes). The area under the receiver operator characteristic curves was significantly different at 0.87 (SE 0.06) for Ceff and 0.63 (0.11) for CET.

CONCLUSIONS: This study confirmed that real-time calculation and display of Ceff based on measured CET values are feasible. We determined the optimum t1/2ke0 for sevoflurane for the effect of cLMA insertion as 2.25 minutes, similar to that determined for loss of consciousness using the raw electroencephalogram. We also showed that Ceff is a more reliable (P < 0.05) guide to successful cLMA insertion than CET.

From the *Department of Anaesthesia, University of Otago: Christchurch and †Department of Anaesthesia, Christchurch Hospital, Christchurch; and Department of Anaesthesia and Intensive Care, Waikato Hospital, Hamilton, New Zealand.

Accepted for publication June 20, 2013.

Published ahead of print September 10, 2013

Funding: Grant from Canterbury Medical Research Foundation and Departmental Funds.

Conflict of Interest: See Disclosures at the end of the article.

This report was previously presented, in part, at the ANZCA ASM, Sydney, May 2008.

Reprints will not be available from the authors.

Address correspondence to Ross Kennedy, MB, ChB, PhD, Department of Anaesthesia, Christchurch Hospital and University of Otago, Christchurch, Rolleston Ave., Christchurch, New Zealand. Address e-mail to

Despite the ubiquitous use of end-tidal concentrations (CET) to titrate inhaled anesthetics, effect-site concentrations (Ceff) are likely to provide a better guide to therapy during rapid changes such as the wash-in and wash-out phases of anesthesia. Effect-site levels allow for the time delay inherent in transfer of drugs from the central (plasma) compartment to the site of action, typically between 2 and 5 minutes. Use of effect-site rather than plasma concentration has become commonplace in the control of IV drugs and may allow better control than either infusion rates or plasma concentrations.1,2 Application of these principles to inhaled drugs are being explored3,4 and show promise.5,6

The traditional measure of anesthetic potency is the equilibrium E50 or median effective concentration. The best known E50 is the minimum alveolar concentration (MAC) and is the concentration at which 50% of subjects respond to a skin incision.7 Derivatives of MAC have been estimated for a wide range of other interventions. These E50 concentrations are estimated after allowing time for equilibrium and should, therefore, be the Ceff required for a given effect. We have previously explored effect-site sevoflurane levels at the point that patients awaken, and showed that, in patients undergoing minor or intermediate surgery, the EC50 for wake up is close to “MAC-awake.”6

Since it is becoming apparent that different effects of the same drug may have different half times,6,8 the utility of using Ceff as a guide to administration is enhanced by knowledge of the appropriate Ceff required for a specific effect. Our aims in this study were to explore sevoflurane requirements for airway insertion during rapid wash-in and to compare these with published EC50 values to derive an estimate of the effect-site half-time for airway manipulation and also to compare the utility of Ceff with CET as a guide to therapy.

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This study was approved by the New Zealand South B Ethics Committee. Subjects were recruited women aged 18 to 66, ASA physical status I, II, or III, without major cardiac or respiratory disease and a body mass index of <30 kg/m2, undergoing surgery and anesthesia for which the anesthesia plan included use of a “classic” laryngeal mask airway (cLMA) and with no contraindication to inhaled induction. Written informed consent was obtained from all participants.

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Data Collection

A Datex ADU anesthetic delivery system (Datex-Ohmeda, Helsinki, Finland) with S/5 monitoring was used for all cases. Data from both the delivery system and monitors were collected and displayed using a locally developed logging and trend display system.9 This system uses the current and past values of the CET to calculate a continuously updated estimate of Ceff. The system used in the current study uses a half-time of sevoflurane diffusion to the effect-site (t1/2ke0) of 5 minutes. After the establishment of routine monitoring, subjects were administered oxygen using a fresh gas flow of 6 L/min oxygen via a circle system. The sevoflurane vaporizer was turned to 6%, and the subject instructed to continue normal tidal ventilation. Time 0 was taken as the time at which sevoflurane was first detected in the sampled inspired gas.

The attending anesthesiologist was instructed to insert the cLMA when the predetermined calculated Ceff, as displayed on our monitoring system, was reached. For the first subject, this was set at 2.5 vol% with succeeding values determined sequentially using an up-and-down methodology based on that first described by Dixon and Mood.10 If a subject showed gross purposeful movement, such as movement of limbs, in response to attempted airway insertion or if airway insertion was impossible, for example, because of excessive jaw tone or gagging, this was scored as a response, and the target concentration was increased by 0.2 vol% for the next subject. Successful airway insertion without gross purposeful movement was scored as a nonresponder, and the target concentration was decreased by 0.2 vol% for the next subject. In the event of protocol or equipment problems with an individual, that subject was not included in the analysis, and the target was unchanged for the next subject. The actual sequence appears in Figure 1. The study period concluded after the first attempt at airway insertion and further conduct of anesthesia was at the discretion of the attending anesthesiologist. Recruitment of subjects continued until 7 pairs of consecutive nonresponders/responders had been observed.

Figure 1

Figure 1

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Analysis of Data

The traditional approach to up-and-down analysis uses the 7 means of the paired nonresponders/responders.10 An alternative approach, which we have used in this study, is the “truncation” method.10 This uses all the individual data points after the first transition from nonresponder to responder. Thus, our main analysis includes all subjects after subject 7 (Fig. 1).

We used the time sequence of measured sevoflurane CET to generate calculated Ceff for 11 values for t1/2ke0 between 0.5 and 5.0 minutes over the time period from first appearance of sevoflurane in the expired gas until the time of the cLMA insertion attempt in each subject. We excluded all data points where the measured end-tidal CO2 was <20 mm Hg. Values for Ceff were calculated using a Visual Basic function for Microsoft Excel that we have used previously.11 This function, which does not require equal time steps, calculates values of Ceff over the time domain of the CET samples for a given value of t1/2ke0. Assuming CET as equivalent to central compartment concentration, then dCeff(t)/dt = ke0 {CET(t) − Ceff(t)} and t½ ke0 = ln 2/ke0.

Figure 2 shows the family of curves for a typical case up until the point the facemask was removed just before cLMA insertion. As can be seen in Figure 2, there is a range of possible values for Ceff at the time of cLMA insertion that depends on the t1/2ke0 used. This can be expressed as a function relating t1/2ke0 to Ceff which is shown in Figure 3 and that plots this relationship in each of the 23 subjects after the first transition from nonresponder to responder. We also plotted the mean (SD) of the derived Ceff values at the point of airway insertion for each of the 11 t1/2ke0 values explored.

Figure 2

Figure 2

Figure 3

Figure 3

To determine an estimate of the Ceff EC50 required for cLMA insertion, we used the data of Kodaka et al.12 and of Tanaka et al.13 who, in separate studies, determined the MAC, or equilibrium EC50, for LMA insertion. We used the mean of these E50 values, 2.17, as the definitive value for Ceff in Figure 3, and from this, we determined the corresponding value of t1/2ke0.

To derive a dose–response probability curve and to compare the utility of Ceff or CET as predictors of response, we performed logistic regression with Ceff and CET as the explanatory variables, using the data from all 30 patients, not just those used for the up-and-down analysis. We used log probit analysis to determine the dose–response curve for Ceff based on t1/2ke0 = 2.25, as derived from Figure 3, and the measured CET at the time of insertion of the cLMA. These curves are shown in Figure 4. We also constructed a receiver operator characteristic curve (ROC) comparing Ceff (t1/2ke0 = 2.25) and CET (Fig. 5). The ROC curve has the advantage of being independent of the probit analysis. The areas under the ROC curves were compared using the empirical (nonparametric) method described by DeLong et al.14 for paired samples. Data analysis was performed using GraphPad Prism for Mac v4.0c (GraphPad Software, La Jolla, CA). Logistic regression was performed by NCSS (version 07.1.13, NCSS, Kaysville, UT).

Figure 4

Figure 4

Figure 5

Figure 5

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Because the analysis involved multiple steps that built on previous steps, the results have been presented graphically in the description of the methodology. Here the results will be reviewed, focusing on content rather than methodology.

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Patient Characteristics

Thirty-eight patients were enrolled between January 2006 and February 2008. Data from 8 patients were unable to be used because of equipment failure in 6 and protocol violation in 2. The 30 remaining patients ranged in age from 22 to 66 years (pooled mean 38). All were ASA physical status I or II (no ASA physical status III patients were recruited) and were scheduled to undergo a range of gynecological procedures. Subjects lost consciousness after a mean (SD) of 99.2 (11.1) seconds (range 60–160 seconds), and, in the group after the first transition, the target for cLMA insertion was reached after a mean time of 256 (SD 57) seconds. In all nonresponders, airway insertion was straightforward.

Figure 1 shows the sequence of responses. The first 7 patients, up to and including the first transition from nonresponder to responder, were excluded from the main analysis, leaving 23 patients. The mean time to reach the chosen level for cLMA insertion in these 23 patients was 259 seconds (95% confidence interval [CI], 236–283 seconds).

Figure 3 shows the calculated Ceff for the 23 patients used for estimation of the t1/2ke0 corresponding to the target EC50 of 2.17 vol% over the range of t1/2ke0 values, along with the mean and 95% CI for each t1/2ke0. From Figure 3, the t1/2ke0 giving a mean Ceff of 2.17 vol% can be derived. The intercept of the curve representing the mean values for each t1/2ke0 with the horizontal value for Ceff of 2.17 vol% corresponds to a value of 2.25 minutes or a rate constant (k) of 0.31 minutes-1. It is also possible to derive the values for t1/2ke0 corresponding to the curves representing the 95% CIs. This construct gives a 95% CI of 2.0 to 2.5 minutes.

Figure 4 shows the sigmoid dose–response curves for the likelihood of response using both Ceff (t1/2ke0 = 2.25 minutes) and sevoflurane CET, using data from all 30 patients for whom the study protocol was completed. The much steeper line for Ceff suggests this is a better predictor of response that is supported by the difference in the area under the ROC curves, as shown in Figure 5, which were 0.87 (SE 0.06) for Ceff and 0.63 (0.11) for CET. This difference was statistically significant (P < 0.05) using the empirical test for the difference between areas. Table 1, derived from the ROC curve analysis, compares the utility of CET and Ceff as guides with successful cLMA insertion.

Table 1

Table 1

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In this study, we were able to determine Ceff sevoflurane for cLMA insertion during rapid wash-in. Based on these results, we derived estimates of E50 for use when an estimate of Ceff is available. Using historical estimates of the equilibrium E50 (MAC) for LMA insertion, we estimate the appropriate t1/2ke0 for this “effect” is approximately 2.25 minutes. These results are broadly similar to those of Schumacher et al.15 who explored propofol/sevoflurane response surfaces for a range of stimuli including LMA insertion and found a mean (SE) value for the sevoflurane EC50 for LMA insertion of 2.55 (0.16) vol% using a t1/2ke0 of 2.4 minutes as determined by Rehberg et al.16

These results also demonstrate that Ceff is a more reliable guide to therapy than CET. This is shown by the difference in the slopes of the dose–response curves (Fig. 4), the difference between the ROC curves, (Fig. 5) and by the large difference between the established E50 (or “MAC”) for this response and the mean end-tidal value of 3.2%. This nearly 50% increase in desired target can be explained by time for effect-site equilibration. These results are in line with our previous exploration of the point at which subjects awaken after sevoflurane anesthesia11 and that of Johnson et al.5 who found that using effect-site sevoflurane levels predicted awakening more reliably than calculations based on CET.

Our estimate for t1/2ke0 for the effect on responses to cLMA insertion is shorter than the t1/2ke0 for the effect on Bispectral Index (BIS), which we have previously determined at 3.2 minutes,11 but is similar to estimates based on changes in the unprocessed electroencephalogram.16 This difference between t1/2ke0 for the effect on the BIS and for the effect of lack of response to airway insertion may, therefore, be due simply to the delay inherent in processed electroencephalogram parameters. An alternative explanation that we,11 and others,8,17 have demonstrated is that different effects have different values for t1/2ke0, in addition to differences in EC50, which is consistent with the concept that these effects occur at different places in the body having different physical characteristics. In addition, different authors, techniques, and study populations produce a range of t1/2ke0 values. For instance, Kreuer et al.18 determined ke0 for the effect of hypnosis, using both BIS and Narcotrend as markers of effect, and found values for sevoflurane equivalent to a t1/2ke0 of 2.6 minutes. In another analysis with a different analytical technique,19 the same group found a t1/2ke0 of 4.3 minutes (ke0 = 0.16).

The estimation of Ceff for inhaled drugs includes a number of assumptions, many of which can be questioned during rapid changes. First is the assumption that end-tidal values are equivalent to central compartment values. Although there are data suggesting that end-tidal to arterial differences are common,20 there has been little formal testing of this effect on the estimation of Ceff, with CET being the accepted marker of central compartment concentrations. The behavior and effect of this gradient has only recently been studied during rapid changes with sevoflurane,21 suggesting that areas of the lung with different ventilation/perfusion ratios transfer inhaled drugs at different rates and reach equilibrium differently. This will mean the increase in arterial concentration will be slower than the increase in CET, suggesting that the transfer from arterial blood to the effect-site is actually faster than the apparent end-tidal to effect-site transfer. This is supported by data exploring the uptake of aerosoled prochlorperazine.22 The second assumption is that the central compartment is perfectly and instantly mixed. This assumption has been shown to break down with rapid or bolus injection of IV drugs.23 Conversely, it may be that the transfer from lung to blood actually acts to dampen changes when compared with an IV bolus. The third assumption is that transport to the effect-site is constant and, in particular, is not affected by changes in cardiac output induced by the drugs themselves. This assumption is also made with IV drugs but has been challenged, especially with the changes occurring around induction of anesthesia.24 Despite these various limitations, the data in the present study along with data from a number of studies and groups would suggest that, in the absence of more direct measures of Ceff, calculations based on CET provide a reasonable estimate of Ceff. There are also several practical considerations with the conduct of the study. During the study period, and in particular around the time of cLMA insertion, values for end-tidal and Ceff were changing as illustrated in Fig. 2. We chose a dial setting of 6% to produce CET that would be changing only slowly at the time of cLMA insertion, but that would still allow the airway to be secured in a timely fashion given we were working in a clinical setting. Our modeling suggested that using a dial setting of 8% would have resulted in sevoflurane CET increasing rapidly at the time of cLMA insertion. Despite this slowing in the rate of rise of CET, the various compartments will not be at equilibrium. As a result, the changes in Ceff during airway insertion are difficult to define. Spontaneous ventilation, maintained in all subjects, will produce a greater change in the composition of gas in the lung than apnea, because room air will be taken into the lungs. Assuming normal minute ventilation and lung volumes, over the 20 to 30 seconds for airway insertion, CET would decrease by, at most, 25%. The actual decrease will be much less than this because of the effect of mixed venous blood. Since Ceff is between one-third and two-thirds of end-tidal at the typical times of airway insertion (Fig. 2), CET, as a marker of central concentration, will remain larger than Ceff. We would expect, therefore, a slight increase in Ceff during this period that from our modeling would suggest an overestimate of t1/2ke0 by no more than 5% to 10%. In addition, many of the assumptions discussed in the preceding paragraph would tend to mitigate against such an overestimate.

The validity of using data from an up-and-down study designed to determine the EC50 in a probit analysis to derive a dose–response curve has been questioned10 because data points at the extremes will be sparse. This type of analysis will tend to underestimate the EC05 to EC95 range. However, a comparison of the curves in Figure 4 provides a clear illustration of the difference between Ceff and CET targeting.

In this study, we have shown that it is possible to derive and display estimates of Ceff in real time and to define an appropriate t1/2ke0 for airway manipulation. We have also provided further support for the thesis that Ceff should be a better guide to therapy than the traditional approach using CET, even allowing for the limitations in the calculation of Ceff. The value of effect-site guided volatile anesthetic delivery deserves further prospective evaluation.

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Name: Ross Kennedy, MB, ChB, PhD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: Ross Kennedy has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Conflicts of Interest: Ross Kennedy reported a conflict of interest with Drager Medical (Speaker in Drager Medical Sponsored sessions with travel support) and consulted for GE Healthcare.

Name: Margie McKellow.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Attestation: Margie McKellow has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Richard French, MB BS.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: Richard French has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Jamie Sleigh, MB, ChB, MD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Jamie Sleigh has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

This manuscript was handled by: Steven L. Shafer, MD.

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This work was funded by a grant from the Canterbury Medical Research Foundation and was presented in part at the Australian and New Zealand College of Anaesthetists ASM, Sydney, Australia, May 2008. Charles Minto provided considerable guidance and advice during the development and analysis of this study and, with Thomas Schnider, developed the visual basic function used for calculating effect-site values for us. Dr. Minto chooses not to be named as an author.

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