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Background. The objective of this study was to develop a pharmacokinetic (PK) model to
Key points characterize the influence of obesity on propofol PK parameters.
† Obesity can alter the Methods. Nineteen obese ASA II patients undergoing bariatric surgery were studied.
pharmacokinetics (PK) of Patients received propofol 2 mg kg21 bolus dose followed by a 5–20–40 –120 min,
drugs and make dosing 10 –8–6–5 mg kg21 h21 infusion. Arterial blood samples were withdrawn at 1, 3, 5 min
difficult. after induction, every 10 –20 min during propofol infusion, and every 10–30 min for 2 h
† Correction from total after stopping the propofol infusion. Arterial samples were processed by high-
body weight (TBW) to performance liquid chromatography. Time– concentration data profiles from this study
lean body mass is often were pooled with data from two other propofol PK studies available at http://www
used but is not always .opentci.org. Population PK modelling was performed using non-linear mixed effects model.
appropriate. Results. The study involved 19 obese adults who contributed 163 observations. The pooled
† The kinetics of propofol analysis involved 51 patients (weight 93 SD 24 kg, range 44– 160 kg; age 46 SD 16 yr, range
target-controlled infusion 25 –81 yr; BMI 33 SD 9 kg m22, range 16– 52 kg m22). A three-compartment model was used
were modelled in obese to investigate propofol PK. An allometric size model using total body weight (TBW) was
patients. superior to all other models investigated (linear TBW, free fat mass, lean body weight,
† An allometric model normal fat mass) for all clearance parameters. Variability in V2 and Q2 was reduced by a
using TBW as the size function showing a decrease in both parameters with age.
descriptor performed Conclusions. We have derived a population PK model using obese and non-obese data to
best in obese patients. characterize propofol PK over a wide range of body weights. An allometric model using
TBW as the size descriptor of volumes and clearances was superior to other size
descriptors to characterize propofol PK in obese patients.
Keywords: anaesthetics i.v., propofol; obesity; pharmacokinetics
Accepted for publication: 17 May 2010
The increasing number of obese patients worldwide has Propofol is commonly used for induction and maintenance
resulted in an increase in surgical procedures in this popu- of general anaesthesia in obese patients.9 – 11 A controversial
lation.1 2 The pharmacokinetic (PK) properties of some drugs issue for propofol dose adjustment in this population has
are known to alter in obesity.3 4 Although body fat has been the selection of an adequate size descriptor to
minimal metabolic activity, fat mass contributes to overall scale PK parameters.12 13 In normal-weight subjects, total
body size and may have an indirect influence on both metabolic body weight (TBW) is often used as a size descriptor.12
and renal clearance. However, the volume of distribution of However, in obese patients, adipose tissue and LBM do not
a drug depends on its physicochemical properties,5 and increase proportionally and the percentage of lean body
there are drugs whose apparent volume of distribution is tissue per kg of TBW decreases.4 13 14 A number of descrip-
independent of fat mass (e.g. digoxin)6 or is extensively tors of body size have been proposed to scale doses in the
determined by it (e.g. diazepam).7 8 Consequently, changes in obese,13 15 but it is unclear which best describes the relation-
body composition in obesity require a strategy for dose ship between propofol dose and its plasma concentrations in
adjustment.2 this population.13
& The Author [2010]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: journals.permissions@oxfordjournal.org
BJA Cortı́nez et al.
Studies of propofol PK in obese are scarce and come from Alemana, Santiago, Chile) and written informed consent,
a small number of patients. A study in eight morbidly obese 19 obese patients undergoing elective bariatric surgery
patients showed that compared with lean adults, the initial were studied prospectively. Patients of ASA .III, with a
volume of distribution was not modified in obese patients.16 history of alcohol or drug abuse, were excluded. Patients
It also found that total body clearance and volume of distri- fasted for at least 8 h before surgery. No premedication
bution at steady state correlated to TBW. The authors con- was given. Propofol was infused using the Anestfusor Serie
cluded that dose schemes based on TBW are the same as II Pro* software (Facultad de Medicina, Universidad de
those in non-obese patients with no risk of accumulation. Chile; http://www.smb.cl/en/anestfusor_serie2_proen.html)
However, this scaling may result in the administration of in a PC Compact Armada 7600. Anaesthetic induction was
largish doses of propofol with the inherent risk of haemo- with a single propofol (10 mg ml21) bolus of 2 mg kg21 at
dynamic adverse consequences. a rate of 20 ml min21. At the same time, remifentanil,
We have investigated propofol PK in obese and non-obese using target-controlled infusion (TCI) (Minto PK model)19
subjects using a population-based approach to predict with an initial plasma target of 5 mg litre21, was started.
sources of the variability in propofol PK parameters. The Rocuronium 0.6 mg kg21 was used to facilitate tracheal intu-
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Propofol pharmacokinetics in the obese BJA
variability in model parameters was modelled by exponen- where BMI is expressed as
tiating random effects (equivalent to assuming a log-normal
distribution). TBW
BMI =
H2
Pi = PTV × ehi
(iii) free fat mass (FFM)
where Pi is the parameter value (e.g. CL and V) of the ith FFM can be predicted from TBW and height (H, m).28
patient, PTV the typical value of the parameter in the popu-
lation, and h the random variable. TBW
FFM = WHSmax × H2 ×
We report the estimate of v for each variability com- WHS50 × H2 + TBW
ponent expressed as a percentage because these quantities
are approximate coefficients of variation for a log-normal For men, WHSmax is 42.92 kg m22 and WHS50 is 30.93
distribution. kg m22 and for women WHSmax is 37.99 kg m22 and
The covariance between two elements of h (e.g. CL and V) WHS50 is 35.98 kg m22.
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BJA Cortı́nez et al.
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Propofol pharmacokinetics in the obese BJA
A A
10 10
9 9
Concentration (mg ml–1)
8 8
7 7
6 6
5 5
4 4
3 3
2 2
1 1
0 0
20 40 60 80 100 140 180 20 40 60 80 100 140 180
Time (min) Time (min)
Fig 1 PC-VPC for the index study. The dashed blue lines present Fig 2 PC-VPC for the pooled analysis. See Fig. 1 for legend.
the 5th and 95th percentiles and the solid orange line depicts the
model predicted median. The shaded grey area is the 90% confi-
dence interval for the prediction percentiles. The 90% prediction The simulation showed that the infusion rates decreased
interval and median for prediction corrected observed data are from 10.9 to 8.8 mg kg21 h21 with the Schnider model, fol-
shown as lines with closed circles. (A) The first 20 min and (B)
lowed by the Marsh model (11.1 to 5.8 mg kg21 h21) and
from 20 to 200 min.
the current pooled model (10.5 to 5.1 mg kg21 h21) to main-
tain the 3 mg ml21 target concentration (Figs 4 and 5). Infu-
sion rates were consistently lower (7.1 to 3.7 mg kg21 h21)
when the Marsh model was used with a weight-corrected
observed data lies within the predicted intervals obtained by formula16 (Fig. 4). In addition, this simulation shows that
simulation. after 3 h of infusion, the predicted context-sensitive half-
Parameter estimates from the pooled study were suitable times were shorter with the Schnider model (0.7 min) com-
for prediction of time –concentration profiles from the index pared with the current pooled model (3.6 min) and longer
study despite parameter estimate differences between the with the Marsh model (8.8 min). The predicted 80% context-
two studies (Fig. 3). Simulated subjects of similar age and sensitive decrement-times were also shorter with the Schni-
weight (n¼1000) to those in the pooled study were given der model (8.2 min) but very close with the pooled model (51
propofol 2 mg kg21 at 200 mg min21. An infusion of 10 mg min) and the Marsh model (55 min) (Fig. 5). To further vali-
kg21 h21 was started at 5 min and ran for 5 min. This was date the anestfusor device used to administer propofol to
then decreased to 8 mg kg21 h21 for 20 min. The infusion study patients and to perform the simulation analysis, we
was further decreased to 6 mg kg21 h21 for the next 30 compared its performance with Rugloop&, a Windows-based
min before slowing to 4.8 mg kg21 h21 for 120 min. The TCI infusion and general data management programme.
figure shows the 90% prediction interval obtained using par- For this, we used the time and the cumulative infusion
ameters from the pooled analysis. Time–concentration pro- (in ml) that anestfusor administered in the TCI simulated
files for the 19 index subjects estimated using individual scenarios and calculated the differences in the predicted
Bayesian parameters obtained from the index analysis concentrations between both devices. The difference was
comply with the 90% prediction interval. negligible with a mean of 0.0006 SD 0.007 mg ml21.
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BJA Cortı́nez et al.
10 3.5
9 Schnider
3.0 Pooled
8 Marsh (TBW)
2.5 Marsh (weight-adjusted)
7
6 2.0
5
1.5
4
3 1.0
2
0.5
1
0 0.0
0 50 100 150 200 250
0 20 40 60 80 105 130 155 180
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Propofol pharmacokinetics in the obese BJA
an allometric relationship between TBW and clearance pro- conclusions regarding covariate models is the rather small
vides a better description in obese patients. Allometric number of patients (n¼51). It has been pointed out that
scaling of clearances using TBW is consistent with other covariate model conclusion will often be subject to selection
studies9 – 11 and simplifies dosage regimes over a wide bias when the number of subjects is ,100.47 Nevertheless,
range of body weights. A recent study of anticancer drugs we cannot find any support for using anything other than
found that the values of CL when normalized to BSA, calcu- TBW as a size predictor for between-patient differences in
lated using TBW, were not significantly different between propofol PK.
obese and lean patients.44 These results further support the Current propofol PK models, used in TCI devices, were
allometric model used in our study because BSA in humans derived from studies that did not include morbidly obese
is approximated with a TBW exponent of 2/3. The allometric patients.17 36 The current recommendation is that TCI
3/4 power model is a non-linear model that has been should be used with caution in the obese.48 The results of
described as a means of predicting physiological function our TCI simulated scenario show that the infusion rates pre-
from body size. Interestingly, a more mechanistic size descrip- dicted by the current pooled model are very similar to those
tor, NFM, showed that TBW (Ffat¼1) rather than using another predicted by the Marsh TCI model using TBW as the input
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BJA Cortı́nez et al.
Acknowledgements 17 Schnider TW, Minto CF, Gambus PL, et al. The influence of
method of administration and covariates on the pharmacokinetics
The authors acknowledge Dr Servin and colleagues16 and of propofol in adult volunteers. Anesthesiology 1998; 88: 1170–82
Dr Schnider and colleagues17 for having shared their propofol 18 Servin F, Desmonts JM, Haberer JP, Cockshott ID, Plummer GF,
data in the open tci initiative (http://www.opentci.org.). Farinotti R. Pharmacokinetics and protein binding of propofol in
patients with cirrhosis. Anesthesiology 1988; 69: 887– 91
19 Minto CF, Schnider TW, Egan TD, et al. Influence of age and
Conflict of interest gender on the pharmacokinetics and pharmacodynamics of
None declared. remifentanil. I. Model development. Anesthesiology 1997; 86:
10–23
20 Plummer GF. Improved method for the determination of propofol
References in blood by high-performance liquid chromatography with fluor-
escence detection. J Chromatogr 1987; 421: 171– 6
1 Kopelman PG. Obesity as a medical problem. Nature 2000; 404:
21 Beal SL, Boeckmann AJ, Sheiner LB. NONMEM Project Group.
635– 43
NONMEM Users Guides. San Francisco: University of California at
Page 8 of 9
Propofol pharmacokinetics in the obese BJA
38 Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics, and 44 Sparreboom A, Wolff AC, Mathijssen RH, et al. Evaluation of alter-
rational opioid selection. Anesthesiology 1991; 74: 53– 63 nate size descriptors for dose calculation of anticancer drugs in
39 Takizawa D, Hiraoka H, Goto F, Yamamoto K, Horiuchi R. Human the obese. J Clin Oncol 2007; 25: 4707– 13
kidneys play an important role in the elimination of propofol. 45 Schnider TW, Minto CF, Shafer SL, et al. The influence of age on
Anesthesiology 2005; 102: 327 –30 propofol pharmacodynamics. Anesthesiology 1999; 90: 1502– 16
40 Takizawa D, Sato E, Hiraoka H, et al. Changes in apparent systemic 46 White M, Kenny GN, Schraag S. Use of target controlled infusion
clearance of propofol during transplantation of living related to derive age and gender covariates for propofol clearance. Clin
donor liver. Br J Anaesth 2005; 95: 643– 7 Pharmacokinet 2008; 47: 119–27
41 Shibutani K, Inchiosa MA Jr, Sawada K, Bairamian M. Accuracy of 47 Ribbing J, Jonsson EN. Power, selection bias and predictive per-
pharmacokinetic models for predicting plasma fentanyl concen- formance of the population pharmacokinetic covariate model.
trations in lean and obese surgical patients: derivation of J Pharmacokinet Pharmacodyn 2004; 31: 109– 34
dosing weight (‘pharmacokinetic mass’). Anesthesiology 2004; 48 Absalom AR, Mani V, De Smet T, Struys MM. Pharmacokinetic
101: 603–13 models for propofol—defining and illuminating the devil in the
42 Rhodin MM, Anderson BJ, Peters AM, et al. Human renal detail. Br J Anaesth 2009; 103: 26–37
function maturation: a quantitative description using 49 James W. Research on Obesity. London: Her Majesty’s Stationary
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