British Journal of Anaesthesia 109 (4): 551–60 (2012)

Advance Access publication 24 June 2012 . doi:10.1093/bja/aes211

Performance of alfentanil target-controlled infusion

in normal and morbidly obese female patients†
O. Pérus 1*, A. Marsot 2, E. Ramain 1, M. Dahman 3, A. Paci 4, M. Raucoules-Aimé 1 and N. Simon 2
1
Pôle Anesthésie-Réanimations, CHU de Nice, Hôpital de l’Archet 2, 151, route de Saint-Antoine de Ginestière, BP 3079, 06202 Nice Cedex 3,
France
2
Service de Pharmacologie Médicale et Clinique AP-HM, Aix-Marseille Université, Marseille, France
3
Service de Chirurgie Viscérale, CHG La Fontonne, Antibes, France
4
Service interdépartemental de Pharmacologie et d’Analyse du Médicament (SiPAM), Institut de cancérologie Gustave Roussy, 114 rue
Edouard Vaillant, 94805 Villejuif cedex, France
* Corresponding author. E-mail: ol_perus@yahoo.fr

Background. Available alfentanil pharmacokinetic (PK) sets for target-controlled infusion

Editor’s key points
† All alfentanil
pharmacokinetic (PK)
models are derived from
populations with normal
BMI.
† Maitre and colleagues’
alfentanil target-controlled
infusion is acceptable for
clinical application to
morbidly obese patients.
† Maitre and colleagues’
model should be applied
with caution to that
population of patients,
especially when
high-concentration targets
are applied.
† Data from this study were
also accurately described
by a new three-
compartment model with
BMI as the covariate.
(TCI) were derived from populations with normal BMI. The performance and accuracy of
the models devised by Maitre and colleagues and Scott and colleagues were evaluated in
a population including morbidly obese patients.
Methods. Alfentanil TCI using Maitre and colleagues’ model was administered to 10
obese and six non-obese women (BMI 19.5 –57.4 kg m22) undergoing laparoscopic
surgery. The initial effect-site target concentration was 100 ng ml21. Alfentanil arterial
plasma concentrations were sampled from TCI onset to 220 min after its termination.
Stanpumpw software calculated predicted alfentanil concentrations. Data were analysed
with a non-linear mixed-effect model (NONMEM, version 7.2), including calculations of
the median performance error (MDPE) and the median absolute performance error
(MDAPE). Scott and colleagues’ model was evaluated retrospectively.
Results. Using Maitre and colleagues’ model, MDPE and MDAPE (range) for the whole
population were 13.3% and 23.9%, respectively. With Scott and colleagues’ model, MDPE
and MDAPE were 230.7% and 50.1%, respectively. We created a three-compartment
model with BMI as the covariate (CL), yielding MDPE 1.1% and MDAPE 30.6%.
Conclusions. Maitre and colleagues’ PK set underestimated the predicted concentrations in
our mixed-weighted population, but its bias and accuracy were acceptable for clinical
application. Scott and colleagues’ model was inaccurate. The NONMEM model seemed to
be more accurate during the infusion and for high concentrations, but it needs to be
validated in a larger population.
Keywords: alfentanil; opioids; overweight; pharmacokinetics; target-controlled infusion
Accepted for publication: 9 April 2012

Obesity induces physiological modifications that are likely non-obese populations. Among these PK sets, Maitre and
to affect drug tissue distribution and elimination.1 In clin- colleagues’3 and Scott and colleagues’4 models are the
ical practice, to avoid the risk of tissue drug accumula- most used in the literature and seem to provide the best
tion,2 the anaesthetist has to rely on short-action accuracy. This study was undertaken to evaluate the accur-
substances. acy of Maitre and colleagues’ and Scott and colleagues’ PK
Among opioids, alfentanil is useful, because of its low sets using the alfentanil PK parameters described by Maitre
liposolubility and its rapid efficacy. The benefits of alfentanil and colleagues3 for morbidly obese and non-obese patients
target-controlled infusion (TCI) may be extended to the undergoing laparoscopic surgery, and to determine a PK
obese population, but the available alfentanil pharmacoki- model describing alfentanil PK parameters in this mixed
netic (PK) models were derived with data obtained from population.
†
Meetings at which the work has been presented: PAGE 2009: Population Approach Group in Europe, Saint Petersburg, Russia, June 23– 26, 2009, abstract no. 1450;
Congrès de la SFAR: Paris, France, September 23– 26, 2009, abstract no. R427; P2T 2010: Congrès de Physiologie, Pharmacologie et Thérapeutique, Bordeaux, France,
March 23–25, 2010, abstract no. 244.

& The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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BJA
Methods
This prospective study was approved by the Nice University
Ethics Committee (Comité de Protection des Personnes se
livrant à la Recherche Biomédicale, CIR 2003 no. 02-035),
and registered with EudraCT (ref: 2011-001439-21). Written
informed consent was obtained from morbidly obese
patients undergoing laparoscopic bariatric surgery, and
normal-weight patients (BMI,30 kg m22) undergoing lap-
aroscopic surgery. Morbidly obese and non-obese female
patients 18 –68 yr old with ASA I or II were eligible for enrol-
ment. Morbidly obese patients undergoing bariatric surgery
had a BMI of .35 kg m22 in combination with a comorbidity,
or a BMI of .40 kg m22 without any comorbidity. BMI was
defined as: body weight (kg)/height2 (m2).
All patients underwent laboratory tests to exclude signifi-
cant illness or pregnancy. Exclusion criteria were: history of
alcohol abuse or illegal drug use, renal or hepatic disease,
gastro-oesophageal reflux, concurrent medication included
drugs known to interact significantly with opioids, or cyto-
chrome P450.
Anaesthesia procedure
One hour before surgery, patients were premedicated with
oral hydroxyzine (100 mg). After local anaesthesia (Emla
& sion (interday precision), expressed as the coefficient of vari-
cream, Astra, Rueil-Malmaison, France), the following blood
vessels were cannulated: one forearm vein for administration
of anaesthetics, a second forearm vein for fluid replacement,
and a radial artery for continuous arterial pressure monitor-
ing and blood samplings. After adequate preoxygenation, an-
aesthesia was induced with a propofol bolus (2.5 mg kg21)
followed after 90 s by alfentanil in the TCI mode. Atracurium
(0.6 mg kg21) was injected i.v. to facilitate tracheal intub-
ation. Anaesthesia was maintained with desflurane, whose
administration was adjusted to obtain the bispectral index
values between 40 and 60. Muscle relaxation was monitored
with a train-of-four nerve simulator.
&
Alfentanil was administered with a BD Pilot Anesthesia
pump (Fresenius-Viale, Brezins, France) connected via a
serial RS-232 interface to a personal computer running Stan-
&
pump software (SL Shafer, Department of Anesthesia,
Columbia University, New York, NY, USA). The PK set for alfen-
tanil described by Maitre and colleagues3 used the total body
weight (TBW) to calculate the physiological parameters. The
initial alfentanil effect-site concentration was set at 100 ng
ml21, and then 60 ng ml21 5 min later. The predicted
target concentrations (effect-site and plasma) and the corre-
sponding alfentanil infusion rate were recorded every 10 s by
&
Stanpump software. During surgery, the target concentration
was adjusted to mean arterial pressure (MAP) and heart rate
(HR): MAP or HR variation exceeding 15% above or below base-
line values induced a 10 ng ml21 increment in the
target alfentanil concentration in the same direction; the pre-
dicted plasma concentration had to reach the predicted effect-
site concentration before a new target could be requested.
Alfentanil target concentration was set at 0 ng ml21 at
552
Pérus et al.
&
pneumoperitoneum exsufflation, and Stanpump software
was stopped after the last blood sample.
Blood sample processing and alfentanil assay
Arterial blood samples (4 ml) for alfentanil concentration
measurements were obtained before a target change 1, 5,
30, 60, and 120 min after starting alfentanil infusion, and
0, 5, 10, 20, 30, 40, 50, 60, 90, 120, 180, and 220 min after
its end. The corresponding predicted plasma and effect-site
alfentanil concentrations of Stanpump software were
recorded at the exact moment of the sampling. All blood
samples were immediately heparinized and centrifuged at
48C, and plasma was separated (3500 rpm for 10 min) and
frozen (–758C) until analysis. Plasma alfentanil concentra-
tions were determined by high-performance liquid chroma-
tography coupled with mass spectrometry in the single
ion-monitoring mode (Département de Pharmacologie Clini-
que, Institut Gustave-Roussy, Villejuif, France). In accordance
with the ICH guidelines, precision (repeatability and inter-
mediate precision) of the method was evaluated. Repeatabil-
ity (intra-day precision), expressed as the coefficient of
variation of repeatability (CVr), was performed for each
level of quality control (QC) six times and intermediate preci-
ation of intermediate precision (CVi), was evaluated for each
level of QC over 5 days. The accuracy was measured by the
deviation or bias (%) of the mean found concentration
(n¼6) from the actual concentration.
The CV values for repeatability (CVr) and for intermediate
precision (CVi) were found between 0.8% and 4.5% and
between 1.1% and 6.0%, respectively. The bias values repre-
senting the accuracy of the method were found below
4.3%.
External validation
Data were analysed using Excel 2003 (Microsoft Corporation,
Seattle, WA, USA). The predictive performance of Maitre and
colleagues’3 PK model of alfentanil was assessed by using
the prediction error (PE).
For each blood sample, the per cent PE of the predicted
plasma alfentanil concentrations was calculated as follows:
Cm − Cp
PE = × 100
Cp
where Cm and Cp are the measured and predicted plasma
alfentanil concentrations, respectively.
As recommended by Varvel and colleagues,5 intrasubject
data analysis consisted of an evaluation of four indicators
of predictive performance for the n subjects:
(i) The median PE (MDPE): the per cent MDPE reflects the
bias of TCI in the ith subject;
MDPEi (%) = median{PEij }, j = 1, . . .
Alfentanil target-controlled infusion and obesity
(ii) The median absolute PE (MDAPE): the per cent MDAPE
indicates the TCI precision in the ith subject.
MDAPEi (%) = median{|PEij |}, j = 1, . . . , Ni
(iii) The divergence: it characterizes performance stability
over time. We used the modified test purposed by
Glen and Servin:6 divergence is defined as the slope
of the signed PE plotted against time, and is
expressed in per cent per hour.
(iv) The wobble: it measures the intrasubject variability of
PE, and is defined as:
Wobble (% min−1 ) = median{PEij − MDPEi },
j = 1, . . . , Ni
where Ni is the number of PE values obtained for the
ith subject.
A second model was evaluated, the Scott and colleagues’4
model. Based on this PK data set and the infusion rates
stored during Maitre and colleagues’ model evaluation, we
calculated the new predicted plasma alfentanil concentra-
tions for each patient. Then, predictive performance was
assessed by using the same method.
Population PK modelling
Population PK analysis was performed using a non-linear
mixed effects model as implemented using NONMEM com-
puter program (version 7.2, ICON Solutions, Dublin,
Ireland).7 The first-order conditional estimation method
was used throughout. Different structural models for alfenta-
nil PKs were investigated: one, two, and three compartments
with linear elimination. Intersubject variability of the differ-
ent PK parameters was estimated with an exponential
error model. Several error models (additive, proportional or
both) were investigated to describe residual variability. The
performance of the model was judged by both statistical
and graphic methods. The minimal value of the objective
function as calculated by NONMEM was also used to assess
the goodness-of-fit. An increase in the goodness-of-fit is ac-
companied by a decrease in objective function, and this
decrease is asymptotically distributed as a x 2 distribution.
Furthermore, standard errors were calculated by the use of
the COVARIANCE option of NONMEM. For graphic model diag-
nostics, the following graphs were compared: observed con-
centrations (depending variable, DV) vs predictions (PRED),
corrected weighted residuals (CWRES) vs time, corrected
weighted residuals vs PRED, individual predictions (IPRED)
vs DV, and normalized predictive distribution error vs PRED
or TIME. Graphics were obtained with R for Windows Soft-
ware (R-2.14.1, The R Foundation for Statistical Computing).
A first analysis was performed to find the base model that
best described the data. Once it was defined, the influence of
each covariate on the PK parameters was tested via an
upward model building. These covariates were height, body
BJA
weight, lean body mass (LBM) calculated with Janmahasa-
tian and colleagues’8 formula, BMI, and age. The diagnostic
plots described above, the change in objective function,
and the change in parameter variability were noted to
select those which improved the model prediction. A de-
crease in the objective function value (OFV) of at least 6.61
(x 2 distribution with one degree of freedom for P,0.01) rela-
tive to the base PK model was required for the addition of a
single parameter in the model. Covariates defined as rele-
vant during the screening step were included in a so-called
‘full model’. Then a backward elimination procedure was per-
formed in which each covariate was removed in turn from
the ‘full model’ and the difference in OFV between the full
and each reduced model was examined. An increase in
OFV .7.88 (P,0.005) was required to retain the covariate
in the final model.
Bootstrap procedures were performed using Wings for
NONMEM (www.wfn.sourceforge.net) to evaluate the 95%
confidence intervals non-parametrically. One thousand boot-
strapped data sets were generated by re-sampling subjects
from the original data set with replacement. These data
sets were analysed using the final model described previous-
ly. Finally, the 2.5th and 97.5th percentiles of the parameter
estimates were taken to build the 95% bootstrap percentile
confidence intervals.
Results
Ten morbidly obese and six non-obese or overweight patients
were included in this study from 2004 to 2007. One non-
obese patient was excluded because of a disconnection
between the computer and the electric pump. No adverse
effect was encountered during alfentanil administration. All
patients were successfully extubated in the recovery room.
Patient characteristic data are reported in Table 1. The
mean BMI for morbidly obese patients was 43 (5.6) kg m22.
Alfentanil infusion duration was in mean 117 (61) min;
total alfentanil dose was 5.3 (2.3) mg. Target-concentration
was modified 3 (0.5) times during alfentanil infusion. The
mean plasma alfentanil concentration measured at the
end of the infusion was 70.9 (5.8) ng ml21.
Figure 1 shows the observed alfentanil plasma concentra-
tion vs time in obese and non-obese patients. The results of
the external validation analysis are reported in Table 2. MDPE
and MDAPE were calculated for obese and non-obese
patients, for three periods: during and after alfentanil infu-
sion, and for the whole study period.
Maitre and colleagues’ model
Maitre and colleagues’ model underpredicted plasma alfen-
tanil concentrations during and after infusion in both obese
and non-obese patients, and the bias differed significantly
from zero. Values of MDPE for the whole population were
13.3%, and of MDAPE were 23.9%. Maitre and colleagues’
PK set performed within acceptable limits during infusion in
obese patients, but only after infusion in non-obese patients.
Figure 2A shows the performance error vs time in obese and
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Table 1 Patient characteristic data

Patient Surgery Age (yr) BMI (kg m22) Alfentanil

Infusion duration (min) Total dose (mg)
1 Gastric bypass 49 42.3 190 7.8
2 Gastric bypass 31 45.7 80 5
3 Gastric bypass 33 42.2 51 4
4 Sleeve gastrectomy 48 57.4 166 7.9
5 Gastric bypass 56 41.2 131 5.6
6 Gastric bypass 48 39 212 7.9
7 Gastric bypass 18 40.7 154 7.1
8 Gastric bypass 37 44.5 136 7.1
9 Gastric bypass 38 38.3 145 7.5
10 Gastric bypass 39 38.9 190 7.6
11 Cholecystectomy 30 21.1 67 3.2
12 Cholecystectomy 54 19.5 49 2.4
13 Cholecystectomy 68 23.9 100 3.5
14 Diagnostic laparoscopy 48 28.9 30 2.3
15 Cholecystectomy 44 26.7 75 3.9

400

Obese
350 Non obese
Measured concentration (mg litre–1)

300

250

200

150

100

50

0
1 5.11 60 120 190 200 210 220 230 240 250 280 310 370 410
Time (min)

Fig 1 Measured alfentanil plasma concentration vs time in obese and non-obese patients, respectively.

non-obese patients for Maitre and colleagues’ model.
Figures 3A and 4A show the predicted vs observed plasma
alfentanil concentrations and the normalized predicted dis-
tribution error vs predicted concentration for the whole
period, respectively.
performance in both obese and non-obese patients (MDPE
were 230.7%, and MDAPE 50.1% for the whole population,
respectively). An acceptable performance of Scott and col-
leagues’ model was only observed during the infusion
period in non-obese patients.

Scott and colleagues’ model NONMEM model

Scott and colleagues’ model underpredicted plasma concen- A three-compartment model with a first-order elimination
trations during infusion in obese patients, and overestimated provided a better description of the data than did a two-
these afterwards. The model showed an overall poor compartment model and was then used as the base

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 Alfentanil target-controlled infusion and obesity
Table 2 Accuracy analysis of Maitre and colleagues’ model, Scott and colleagues’ model, and the NONMEM PK model. Values are percentages. MDPE, median of performance error (bias);
MDAPE, absolute median of performance error (accuracy). Divergence is expressed as % min21

Maitre and colleagues’ model3 NONMEM model Scott and colleagues’ model4
MDPE MDAPE Wobble Divergence MDPE MDAPE Wobble Divergence MDPE MDAPE Wobble Divergence
Obese patients
Infusion
Mean 25.5 36.5 12.3 20.7 22.6 12.4 7.2 0.0 38.3 40.6 20.2 20.4
25th; 75th percentiles 11.9; 40.9 24.5; 43.1 8.5; 21.9 20.9; 20.4 237.8; 16.7 4.6; 37.8 2.5; 18.6 0.0; 0.0 18.3; 49.9 38.3; 50.3 14.8; 27.1 20.5; 20.2
After infusion
Mean 40.1 26.8 7.6 0.2 8.4 37.8 6.0 0.0 245.1 48.6 12.6 0.1
25th; 75th percentiles 211.4; 42.2 13.3; 42.2 4.5; 11.7 0.0; 0.3 258.5; 77.8 6.5; 80.4 1.1; 26.8 0.0; 0.0 258.7; 55.8 43.3; 100.5 7.2; 32.0 0.1; 1.1
Whole period
Mean 31.1 23.8 11.2 20.1 2.2 25.9 9.4 0.0 225.9 52.4 23.0 0.1
25th; 75th percentiles 29.7; 37.5 13.3; 40.5 7.9; 14.3 20.2; 0.1 257.8; 65.3 6.4; 77.1 4.0; 32.1 0.0; 0.0 252.0; 218.7 43.3; 61.7 14.5; 31.9 0.0; 0.1
Non-obese patients
Infusion
Mean 43.6 43.6 10.8 20.6 37.4 40.5 20.4 0.0 215.1 16.5 9.1 0.1
25th; 75th percentiles 7.0; 86.4 25.6; 86.4 4.3; 27.1 25.4; 0.0 214.6; 83.0 20.7; 83.0 6.0; 29.8 20.1; 0.1 216.5; 26.0 15.5; 33.6 7.4; 15.5 20.7; 0.7
After infusion
Mean 216.1 34.2 6.2 0.0 212.9 36.7 8.5 0.0 246.2 46.2 13.4 0.1
25th; 75th percentiles 231.0; 51.8 31.0; 51.8 5.9; 9.5 0.0; 0.4 234.1; 69.2 21.4; 69.2 5.6; 21.2 0.0; 0.0 272.2; 210.9 45.9; 74.2 11.8; 36.6 0.1; 0.4
Whole period
Mean 23.9 23.9 8.6 0.1 29.5 36.7 12.1 0.0 242.6 47.7 20.9 0.0
25th; 75th percentiles 3.0; 89.6 7.7; 89.6 6.1; 9.5 0.0; 0.2 232.1; 68.6 21.4; 68.6 6.3; 21.7 0.0; 0.0 268.6; 216.1 43.2; 68.6 14.7; 21.1 0.0; 0.2

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A 400
350
300

Performance error (%)

250
200
150
100
50
0
–50
–100
–150
1 5 60 120 145 155 165 175 185 195 205 235 265 325
Time (min)

B 400
350
300
Performance error (%)

250
200
150
100
50
0
–50
–100
–150
1 5 60 120 190 200 210 220 230 240 251 310 370
Time (min)

Fig 2 Performance error vs time for Maitre and colleagues’ model (A) and NONMEM model (B) for obese (solid lines) and non-obese patients
(dotted lines).

model. The interindividual variability (IIV) was retained for
clearance (CL), volume of compartment 1 (V1), clearance of
compartment 2 (Q2), clearance of compartment 3 (Q3), and
volume of compartment 3 (V3) and were modelled as expo-
nential. An exponential model for the residual variability
ensured a good adequacy between the observed and pre-
dicted values. During the selection process, we found that
BMI was a significant factor influencing the IIV in clearance
(CL). Between the base and the final model, the OFV
decreased by 15 units and the intersubject variability on
clearance from 61.1% to 51.1% (10.0%). None of the other
covariates tested was retained. The relationship observed
between BMI and CL is described in Figure 5. The final PK
estimate parameters and 95% confidence intervals obtained
from the bootstrap procedures are summarized in Table 3.
h-Shrinkage was evaluated for the parameters for which
IIV was identified, since poor individual estimates of the
parameter could result in distorted parameter –covariate
relationship:9 h-shrinkage values were 1.06% for CL, 7.9%
for Q2, 4.8% for Q3 and 28.7% for V3, respectively.
Figure 2B shows the performance error vs time in obese
and non-obese patients for the NONMEM model. Figures 3B
and 4B show the predicted vs observed plasma alfentanil
concentrations and the normalized predicted distribution
error vs predicted concentration for the whole period,
respectively.
Discussion
Clinical outcomes of patients anaesthetized with TCI and its
accuracy should be used to select a PK set. It was shown
that a mean 20 –30% variation of measured concentrations
above or below targeted concentrations with a maximum of
50–60% can be considered clinically acceptable.10 Different
possible sources of variability are encountered when using a
PK model for TCI, especially if patients receiving TCI do not
belong to the same population as that used to develop the
original PK model. In morbidly obese patients, PK changes
have been reported for highly lipophilic drugs.11 12

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Alfentanil target-controlled infusion and obesity BJA

A B
120
Predicted concentrations (mg litre–1)

Predicted concentrations (mg litre–1)

100 300

80
200
60

40
100

20

0
0 50 100 150 200 250 300 350 0 50 100 150 200 250 300 350
Observed concentrations (mg litre–1) Observed concentrations (mg litre–1)

Fig 3 Correlation between predicted and measured alfentanil concentrations for the whole period using Maitre and colleagues’ model (A) or
NONMEM model (B). The solid line represents the ideal correlation as opposed to that obtained.

A 3 B

2
2

1
1
npde

0
npde

–1 –1

–2 –2

–3 –3
20 40 60 80 100 120 0 50 100 150 200 250 300 350
Predicted concentrations (mg litre–1) Predicted concentrations (mg litre–1)

Fig 4 Plot of the normalized predictive distribution errors (NPDE) vs predicted alfentanil concentration with Maitre and colleagues’ model (A) or
NONMEM model (B). The solid line represents the ideal correlation as opposed to that obtained.

Only a few studies are available concerning the adminis- alfentanil, during the intraoperative period13 – 16 18 and/or
tration of alfentanil in the TCI mode,13 – 18 and ours is the for postoperative analgesia.13 14 17
first one evaluating an alfentanil TCI in a population includ- According to Coetzee and colleagues,10 our MDPE and
ing obese patients. However, the small number of our MDAPE overall values of 13.3% and 23.9%, respectively, for
patients induced limitations for covariate analysis,19 and the whole period with Maitre and colleagues’ PK set would
probably contributed to alter the results of Maitre and be sufficient to provide acceptable accuracy for clinical use.
colleagues’3 and Scott and colleagues’4 PK sets performance, Our alfentanil plasma concentrations provided good residual
especially in non-obese patients (Table 2). analgesia, and according to Stanski and Hug,20 an alfentanil
We selected Maitre and colleagues’ PK model because it concentration of 100 ng ml21 is sufficient to provide spon-
was used in all previous studies on TCI administration of taneous ventilation.

557
BJA Pérus et al.

Van den Nieuwenhuyzen and colleagues obtained similar
results. They successfully used Maitre and colleagues’ PK
set for postoperative analgesia in three different studies,
and found excellent bias and accuracy values.13 14 17 In
their first studies,13 14 alfentanil was administered during
surgery targeting plasma concentrations (400 and 150 ng
ml21, respectively), and blood samples were collected exclu-
sively after operation. The median values of minimal effective
analgesic concentrations were in a range 43– 65 ng ml21.
Even though no adverse effect was described in the other
studies, the predictive performances of Maitre and collea-
gues’ PK model differed markedly.
0.7
0.6
Clearance (litre min–1)
Barvais and colleagues16 compared nine different PK set in
eight volunteers during a 4 h alfentanil infusion at 50 ng ml21.
All PK sets, except Scott and colleagues’ model which slightly
overpredicted concentrations, underestimated plasma alfen-
tanil concentrations. Maitre and colleagues’ MDAPE was
inaccurate, exceeding 50%. The authors concluded that PK
models derived from patients receiving a large and rapid
bolus injection were not accurate for alfentanil TCI adminis-
tration, and recommended to use models derived from a
slow injection. These findings were confirmed in the elderly
in another study.18
Others15 found Maitre and colleagues’ PK set to have poor
predictive performance with MDPE and MDAPE values at 53%
in two groups of patients, resulting in underestimations of
alfentanil concentrations. The initial plasma concentration
target was 100 ng ml21 for the first group, and the second
group had sequential concentrations from 400 to 700 ng
ml21. Arterial blood samples were collected during the
intraoperative period. Those authors stopped their investiga-
tion of Maitre and colleagues’ model after 11 patients from

0.5 the second group because of the poor bias and accuracy
values, and pursued the study with Scott and colleagues’
0.4 PK set, which yielded better results. The authors did not
find a complete explanation for the differences observed in
0.3 the two PK parameter sets, but found that the inaccuracy
of Maitre and colleagues’ model was high after changing
0.2 the target concentration.
We observed similar results in our study, when we com-
0.1
pared the Maitre and colleagues’ model bias and accuracy
during the different periods of alfentanil infusion: perform-
20 30 40 50 ance was poorer after changing the target concentration,
Body Mass Index (kg m–2) and at the onset of alfentanil infusion: the plot of predicted
vs observed concentrations (Fig. 3A) showed a good correl-
Fig 5 Correlation with NONMEM model between BMI and CL. ation for concentrations below 110 ng ml21, but a lack of
fit for higher concentrations for which the model

Table 3 Population PK parameters of alfentanil NONMEM model [values (SE)]. CL, clearance; V, volume of distribution; Q, clearance
of the compartment

Parameter Basic model Final model 1000 bootstrap replicates

Mean estimate %SE Mean estimate %SE Mean estimate 2.5 –97.5% quantiles
21
CL (litre min ) 0.226 15.3 — — — —
CL (litre min21)¼n1 ×BMI — — 0.245 0.243 0.178– 0.303
n1 — — 0.00647 12.4 0.00641 0.00469 – 0.00791
V1 (litre) 3.67 8.6 2.70 7.2 3.33 2.70 –4.20
Q2 (litre min21) 1.35 13.7 1.71 21.1 1.44 0.94 –1.95
V2 (litre) 10.30 7.2 9.28 9.2 10.71 9.15 –12.6
Q3 (litre min21) 0.331 22.2 0.389 15.7 0.360 0.266– 0.464
V3 (litre) 36.3 15.9 38.6 13.6 44.9 27.5 –65.3
v 2CL 0.611 48.4 0.511 32.9 0.453 0.268– 0.644
v 2V1 0.285 37.9 — — — —
v 2Q2 0.573 28.2 0.619 36.6 0.525 0.174– 0.757
v 2Q3 0.605 41.3 0.560 42.4 0.503 0.030– 0.773
v 2V3 0.349 48.5 0.310 46.3 0.542 0.204– 0.812
Residual variability, s 2 0.116 22.7 0.123 22.2 0.137 0.098– 0.184

558
Alfentanil target-controlled infusion and obesity
underestimated the observed concentrations. We chose to
target the alfentanil effect-site concentration, because of
the difficulty of rapidly modifying the drug effect while tar-
geting the plasma, as each increase in the effect-site
target induced a consequent peak plasma alfentanil
concentration.
The performance of Maitre and colleagues’ model was
particularly bad at the first sample, 1 min after the start of
alfentanil infusion (the only one sample realized before
effect-site and plasma target concentration equilibration),
and some hypothesis may explain this situation. Mertens
and colleagues21 compared alfentanil PKs during a continu-
ous infusion, alone, or with a continuous infusion of propofol
started 10 min before the start of alfentanil infusion: propofol
altered alfentanil PKs, increasing alfentanil plasma concen-
trations, including the initial alfentanil plasma peak. In our
study, a single propofol bolus was injected during induction
90 s before the start of alfentanil infusion, and it probably
contributed to increase the initial alfentanil plasma peak.
On the other hand, the technique of blood sampling may
play an important role on possible artifacts: some authors
recommend to evaluate PK studies of drugs using arterial
samples, observing that venous concentrations are lower
than arterial concentrations;10 22 conventional compartment
models assume that drug added in the central compartment
is instantaneously completely mixed and appears in the ar-
terial concentration, but in practice, this is false, and this is
a reason why PK models do not perform well in the first
minutes.23 For drugs undergoing tissue elimination such as
remifentanil, it was observed that venous sampling reflected
more exactly the effect compartment concentrations.24
We also observed that Scott and colleagues’ model
performed within acceptable performance in non-obese
patients during alfentanil infusion. This PK set seemed to
be more accurate than Maitre and colleagues’ one for high
concentrations, but it did not perform with sufficient preci-
sion in obese patients, and during the post-infusion period
in both populations.
These observations could explain the poor results
obtained by Raemer and colleagues,15 because they used
much higher alfentanil target concentrations than van den
Nieuwenhuyzen and colleagues,13 14 who began blood
sampling at lower alfentanil concentration.
The NONMEM population PK model seemed to be more
accurate during the infusion and for high concentrations.
But because of the small size of our population, it needs to
be retested and validated in a larger population of patients,
including men. Despite the relationship between BMI and
CL, IIV observed with our model is relatively high. Maitre
and colleagues devised their model based on data from 45
non-obese patients,3 and validated it for 19 non-obese
patients:25 their PK –pharmacodynamic analysis identified
three variability factors: age, sex, and weight.
Entering a modified weight on the TCI device system could
improve the reliability of the PK set: Egan and colleagues11
showed that administering a lean-person dose of remifenta-
nil to an obese patient induced an excessively high plasma
BJA
concentration, and recommended to adjust remifentanil
dose to LBM. But the problem is that existing LBM formulas
or nomograms are not applicable to obese patients,
because of the lack of data.26 Anaesthesiologists must find
a compromise between IBW, and TBW for drug administra-
tion to obese patients. La Colla and colleagues27 described
in a case report a super-obese patient in whom remifentanil
was successfully administered in the TCI mode using the
IBW. Servin and colleagues28 suggested an adjusted IBW
formula for propofol administration, but finally, it seemed
that the performance of the TCI device system was better
with propofol administered using TBW.27 For sufentanil, we
previously demonstrated that TCI administration using TBW
was accurate for obese patients with the PK set described
previously.29
Because of its pharmacological properties, alfentanil has
lower clearance and far less redistribution than sufentanil;
it could be administered as a function of LBM. But repeating
our analyses with LBM showed no improvement for Maitre
and colleagues’ model. Our results suggest that the concen-
tration predicted by Maitre and colleagues’ model was under-
estimated, which may lead to overdosing alfentanil for obese
patients. In conclusion, the accuracy of the PK model
described by Maitre and colleagues3 for alfentanil TCI is ac-
ceptable for clinical application to morbidly obese patients,
but it should be applied with caution to that population of
patients, especially when high-concentration targets are
applied.
Declaration of interest
None declared.
Funding
This study was fully supported by the University Hospital of
Nice, as part of an incentive contract for Clinical research
(CIR 2003).
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