British Journal of Anaesthesia 99 (2): 25261 (2007)

doi:10.1093/bja/aem135 Advance Access publication June 19, 2007

PAEDIATRICS
Remifentanil midazolam sedation for paediatric patients receiving
mechanical ventilation after cardiac surgery
A. E. Rigby-Jones1, M. J. Priston2, J. R. Sneyd1 *, A. P. McCabe3, G. I. Davis3, M. A. Tooley4,
G. C. Thorne5 and A. R. Wolf 3 6
1
Anaesthesia Research Group, Peninsula Medical School, Plymouth, UK. 2Department of Pharmacy,
Derriford Hospital, Plymouth, UK. 3Bristol Royal Childrens Hospital, Bristol, UK. 4United Bristol
Healthcare Trust, Bristol, UK. 5Department of Medical Physics, United Bristol Healthcare Trust, Bristol, UK.
6
Department of Anaesthesia and Critical Care,
University of Bristol, Bristol, UK
*Corresponding author. E-mail: robert.sneyd@pms.ac.uk

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Background. Sedation of critically ill children requiring artificial ventilation remains a thera-
peutic challenge due to large individual variation in drug effects and a paucity of knowledge of
pharmacokinetics in this population. This study aimed to determine the pharmacokinetics of
remifentanil in children requiring ventilation after cardiac surgery.
Methods. Twenty-six ventilated children aged 1 month to 9.25 yr (median 1.77 yr) who had
undergone cardiac surgery were sedated with a fixed rate infusion of midazolam 50 mg kg21
h21 and a remifentanil infusion that was commenced at 0.8 mg kg21 min21 for a minimum of
60 min and subsequently decreased by 0.1 mg kg21 min21every 20 min until the patient awoke.
Arterial blood concentrations of remifentanil and midazolam were measured using high-
performance liquid chromatography. Mixed-effects population models were fitted to the
remifentanil concentration time data.
Results. Satisfactory sedation was achieved in all patients as assessed by Comfort score during the
initial maintenance and reduction phase of the remifentanil infusion. One patient was withdrawn
from the study due to hypotension. Remifentanil pharmacokinetics were best described using a
two-compartment allometric model. For a typical child with a body weight of 10.5 kg, clearance
was 68.3 ml kg21 min21, intercompartmental clearance was 80 ml kg21 min21, the central com-
partment volume was 91.7 ml kg21, and the peripheral compartment volume was 141 ml kg21.
Conclusions. A combination of remifentanil and midazolam provided satisfactory sedation for
these patients. Owing to enhanced clearance rates, smaller (younger) children will require higher
remifentanil infusion rates than larger (older) children and adults to achieve equivalent blood
concentrations.
Br J Anaesth 2007; 99: 25261
Keywords: analgesics opioid, remifentanil; children; hypnotics benzodiazepines, midazolam;
pharmacokinetics remifentanil; sedation
Accepted for publication: April 14, 2007

Children in intensive care require analgesia and sedation
to tolerate artificial ventilation. The drugs most commonly
used in the paediatric intensive care unit (PICU) are an
opioid (morphine or fentanyl) in combination with a
benzodiazepine (midazolam or lorazepam). There are only
a limited number of drugs available for sedation on PICU,
and they are all associated with significant side-effects.1
Opioid use is associated with ventilatory depression,
delayed return of bowel function, withdrawal symptoms,
and dose-dependent effects on immunity.2 Midazolam is
Presented in part at the Anaesthetic Research Society Summer
Meeting, Sheffield, UK, July 2005 (Br J Anaesth 2005; 95: 578P9P),
and at Euroanaesthesia, Madrid, June 2006 (Eur J Anaesthesiol 2006;
23(S37): 171).

# The Board of Management and Trustees of the British Journal of Anaesthesia 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
 Remifentanil sedation in paediatric intensive care
also associated with withdrawal3 and delayed recovery
after longer-term use.4 Propofol was withdrawn as a seda-
tive agent in PICU due to the risk of a syndrome charac-
terized by bradycardia and rhabdomyolysis,5 6 the loss of
this useful agent has increased the need for a new
approach to sedation in PICU. A potential alternative is
remifentanil which, in adults, has an onset of action of
about 1 min7 and an elimination half-life of less than 10
min that is virtually independent of age, organ function,
and infusion duration. Remifentanil has been used success-
fully as a sedative agent in children8 9 and adults,10 and
has clinical potential in PICU.
This study aimed to determine the pharmacokinetics of
remifentanil in children requiring ventilation after cardiac
surgery and to seek correlations between processed elec-
troencephalogram (EEG) derivatives, measured and pre-
dicted remifentanil concentrations, and a standard PICU
sedation scale, the Comfort Score.
Methods
Patient population
The study population comprised children scheduled for
elective cardiac surgery. The study was approved by the
Local Ethics Committee, and written informed consent
was given by the childs parents or legal guardian. The
study was conducted at Bristol Childrens Hospital
between March 2003 and February 2005.
Children who were undergoing simple cardiac surgery
were included in the study. Children with existing neuro-
logical deficits or significant cognitive impairment and
children requiring postoperative muscle relaxants were
excluded from the study. Patients were excluded if pro-
longed postoperative ventilation or major inotropic support
was anticipated.
Conduct of anaesthesia
After premedication with oral diazepam (0.5 mg kg21),
anaesthesia was induced with sevoflurane and maintained
with isoflurane (0.10.5%) except during cardiopulmonary
bypass (CPB). Fentanyl was administered on induction as a
bolus dose of 5 mg kg21 followed by an infusion of 25 mg
kg21 h21 reduced to 10 mg kg21 h21 after 1 h. Pancuronium
0.1 mg kg21 was administered on induction. For bypass
cases, a standardized CPB circuit was used and midazolam
0.5 mg kg21 and pancuronium 0.1 mg kg21 added to the
prime solution. The fentanyl infusion was increased to
15 mg kg21h21 during CPB. After CPB had been discontin-
ued, a loading dose of midazolam 0.1 mg kg21 was adminis-
tered and the fentanyl infusion was discontinued. In
non-bypass cases, fentanyl was given as above, but was
maintained at 10 mg kg21 h21 until chest closure when the
fentanyl was discontinued and midazolam (0.1 mg kg21)
given. Hypothermic CPB was not used. Normothermia was
253
maintained except in coarctation patients in whom tempera-
ture was allowed to drift to no lower than 348C.
Haemodynamic management
Arterial blood pressure was monitored invasively in all
cases. Vasodilating drugs (sodium nitroprusside or miliri-
none) were given according to independent direction from
the intensive care and cardiology teams. Hypotension was
defined as a persistent reduction in mean blood pressure
by more than 20%. Hypotension was treated either with
volume replacement (in aliquots of 5 ml kg21 or according
to central venous pressure management) or with ino-
tropes (dopamine 5 10 mg kg21 min21 or epinephrine
0.1 0.5 mg kg21 min21) if there was evidence of impaired
ventricular function (increased arterial lactate and decreased
venous saturations).
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Sedation on PICU
On arrival on PICU, midazolam was infused at 50 mg
kg21 h21 and this was continued throughout the study
period. A remifentanil infusion was commenced at 0.8 mg
kg21 min21 and maintained at this rate for a minimum
period of 1 h. After this time and when the patient was
free from neuromuscular block, normothermic and stable
haemodynamically, the rate of remifentanil infusion was
decreased to 0.7 mg kg21 min21 and blood samples were
collected during the subsequent 25 min. The remifentanil
infusion rate was then decreased by 0.1 mg kg21 min21
every 20 min until the patient awoke.
Arousal was pre-defined as the combination of eye-
opening and spontaneous limb movement. Immediately
after arousal, the remifentanil infusion rate was increased
to 0.3 mg kg21 min21, and sedation and analgesia
increased with i.v. bolus doses of morphine 100 mg kg21
and midazolam 200 mg kg21. A morphine infusion was
started at 20 mg kg21 h21. Remifentanil was discontinued
15 min after commencing the morphine infusion and the
remifentanil infusion line flushed clear of drug.
Blood sampling
Pharmacokinetic simulations (WinNonlin v1.5, Pharsight
Corporation, CA, USA) using parameter values derived
from a similar study population11 were used to create an
informative sampling scheme. The partial derivatives of
the predicted function (i.e. the mathematical function
describing a two-compartment pharmacokinetic model)
with respect to each of the model parameters were plotted
against time to reveal any turning points (local maxima or
minima). Blood samples obtained at the time of these
turning points will contribute the maximum information
on that particular parameter.12 Having identified key
sampling time zones, we then compared various sampling
designs and selected those that were associated with
smaller variance inflation factors (indicative of an
 Rigby-Jones et al.
Fig 1 Summary of the drug infusion and blood-sampling schedules. The
solid line shows the remifentanil infusion scheme during our study
(time=0 indicates the beginning of the remifentanil infusion). The broken
line represents the midazolam infusion rate. The black markers show
typical blood-sampling time points. Three samples were collected during
the first 25 min of remifentanil infusion. A further three samples were
collected during the 20-min period after the first reduction in remifentanil
infusion rate. Additional samples were obtained 20 min after the second
and subsequent reductions in the remifentanil infusion rate and at the
point of arousal.
expected reduction in the variance of the estimates of the
pharmacokinetic parameter values compared with
sampling schemes with higher variance inflation factors).
All blood samples were arterial. A baseline blood sample
was collected before the first administration of remifentanil.
Three samples were collected during the first 25 min of
remifentanil infusion; nine sampling points were divided
into three sampling blocks (1, 2, or 3 min), (5, 8, or 10
min), (15, 20, or 25 min), and each patient was randomized
to one sampling time per block. A further three samples
were collected during the 20 min after the first reduction in
remifentanil infusion rate when again, each patient was ran-
domized to one sampling time per block (1, 2, or 3 min), (5,
8, or 10 min), (12, 15, or 20 min). Further samples were
obtained 20 min after the second and subsequent reductions
in remifentanil infusion rate (up to a maximum of five
samples) and a final sample was collected at the point of
arousal. Figure 1 summarizes the remifentanil infusion rate
changes and the blood-sampling scheme.
Sample handling and drug assay
Whole blood samples (1 ml) were collected using lithium
heparin blood gas analysis syringes and decanted into
polypropylene tubes containing 20 ml of citric acid 50%
(w/v) to prevent further metabolism of remifentanil by
plasma esterases.13 The samples were immediately frozen
in liquid nitrogen and then stored at 2808C before assay.
Remifentanil, fentanyl, and midazolam were extracted
from 900 ml whole blood using a liquid liquid extraction
technique13 and quantified using a novel high performance
liquid chromatography method. See the appendix for
details of the assay methodology. The assay had proven
254
linearity for remifentanil in the range 1 25 ng ml21
(R 20.997). Intra-day precision (coefficient of variation,
n5) for remifentanil was 9% at 1 ng ml21 and at 10 ng
ml21 and 2% at 20 ng ml21. Inter-day precision was
,10% at 5, 10, and 20 ng ml21 (n7). The limit of
quantification for remifentanil was 1 ng ml21.
Assessment of sedation
Sedation status was assessed approximately every 10 min
using the Comfort Scale scoring system.14 Comfort scores
are used routinely in our practice and data collection for
the present study was restricted to one of two trained
PICU research nurses.
EEG recordings were made continuously from electro-
des at C3P3 and C4P4 using standard equipment (Nicolet
Pathfinder).
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Pharmacokinetic analysis
Mixed-effects population models15 were fitted to the remi-
fentanil blood concentration vs time data. The program
NONMEM version V16 was used. Models were fitted
using the first order conditional estimation method with
interaction between the interindividual error terms (ETAs)
and the random residual error term allowed. The random
residual error was described using an additive error model.
A Compaq Digital Fortran V6.6 compiler was used with
an Intel Centrino 1.7 GHz CPU (Intel, Santa Clara, CA,
USA) under Microsoft Windows XP Professional
(Microsoft, Seattle, WA, USA).
The data were first applied to one-, two-, and three-
compartment mamillary models. A two-compartment
model was superior to a one-compartment model, but a
three-compartment model did not further improve the
model fit. The selected two-compartment model was
developed by adding ETA parameters to each structural
parameter until no further model improvement could be
justified, according to the goodness-of-fit criteria described
later. A proportional variance model was used to describe
the interindividual variability. Next, guided by diagnostic
plots and generalized additive modelling using S-PLUS
and Xpose software,17 we examined models which
allowed the structural pharmacokinetic parameters to differ
with covariates. We systematically modelled each struc-
tural model parameter as a simple ( proportional) and as
complex (linear, power, and fixed allometric) functions of
age and body weight. For the allometric function, par-
ameter values were standardized for a body weight of
10.5 kg (the median patient weight in our study) as
follows:
 
WTi POWER
PiP
WTMED
Pi describes the parameter value in the ith individual, WTi
is the weight of the ith individual, and P is the parameter
 Remifentanil sedation in paediatric intensive care
value in an individual with a body weight (WTMED) of
10.5 kg. The value of the power exponent (POWER) was
fixed to 0.75 for clearance parameters and to 1.0 for
volume parameters in accordance with established biologi-
cal scaling laws.18 CPB was examined as a dichotomous
covariate. Hence, in models evaluating the influence of
CPB, the pharmacokinetic parameters were allowed to
assume different values in bypass and non-bypass patients.
The statistical significance of each proposed covariate
parameter relationship and the requirement for ETA par-
ameters was assessed using the likelihood ratio test (where
appropriate, i.e. for nested models) and by consideration
of the Akaike Information Criterion (non-nested models)
and the precision of the final parameter estimates (all
models). For nested models, the justification for each
additional effect was for it to improve the goodness-of-fit
statistic (22 log-likelihood) by more than 3.84 (evaluated
against the x2 distribution, this is equivalent to signifi-
cance at the 0.05 level). The improvement (or lack of ) in
model goodness-of-fit was also assessed visually by the
examination of diagnostic plots. After completing the
model build, the necessity for each added component was
assessed by removing it from the model and evaluating the
impact on the resultant model fit.
Model evaluation
The median prediction error and median absolute predic-
tion error were calculated for our final population model
as described by Varvel and colleagues.19 The predictive
performance of our model was also evaluated using lever-
age analysis and bootstrap simulations. For the leverage
analysis, multiple data sets were produced each of which
excluded one patient from the analysis, a different patient
being excluded from each data set. Our final population
model was applied to each data set and the parameter esti-
mates compared with the estimates resulting from the
analysis of the entire data set to identify any individuals
who may have exerted a large influence on the parameter
values. The software Wings for NONMEM (WFN v409,
N. Holford, University of Auckland)20 was used to
perform a bootstrap analysis. One thousand bootstrap data
sets were created by sampling the data, with replacement,
from the original data set. Our final pharmacokinetic
model was then fitted to each of the resulting data sets.
The mean parameter values and the 2.5 and 97.5 percen-
tiles for all successful runs (where the model minimized
successfully and the covariance step was completed) were
determined, and the difference between the bootstrap
mean and the NONMEM estimate obtained from original
data set was calculated.
Simulations
To investigate our findings, pharmacokinetic simulations
were performed using the typical population parameters of
255
our final model. Concurrently, we performed simulations
using previously published kinetic models for remifentanil.
This allowed comparison of our model with a model
developed from a similar patient population11 and with a
model based on data from healthy adults.21 Remifentanil
blood concentration vs time profiles resulting from
a 60 min infusion of remifentanil at a constant rate of
0.8 mg kg21 min21 were simulated.
Sample size
Study size was determined pragmatically based on our pre-
vious experience with pharmacokinetic studies in small
children,22 anticipated recruitment, and feasible number of
samples for assay.
Results
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We studied 26 children aged 0.08 9.25 (median 1.77 yr),
weight range 3.1 39.8 kg (median 10.5 kg). Surgical
procedures included ASD repair, VSD repair, Glenn
Shunt, mitral valve repair, and atrial septectomy (Table 1).
Twenty-one children underwent CPB. The CPB time
ranged from 19 to 83 min [mean 46 (SD 15) min].
Remifentanil infusion duration ranged from 19 min to
20.6 h (median 194 min). Patient 2 required overnight seda-
tion at a remifentanil infusion rate of 0.8 mg kg21 min21
before the criteria for the step-down rate sequence were
met, hence the extended remifentanil infusion duration.
Safety
Patient 3 was withdrawn from the study. After commence-
ment of remifentanil, blood pressure decreased from 71/47
to 59/39 mm Hg in 3 min. Norepinephrine infusion at
0.1 mg kg21 min21 and fluid bolus (60 ml) were mini-
mally effective and the remifentanil infusion was stopped
after 19 min. Two minutes after stopping the infusion,
blood pressure returned to 72/49 mm Hg. The early blood
samples obtained from this child, before withdrawal from
the study, were assayed and included in the pharmacoki-
netic analysis.
A further two children became hypotensive after com-
mencement of remifentanil infusion (Table 1). One settled
spontaneously, the other responded to fluids.
Sedation scores
Satisfactory sedation was achieved and maintained in all
patients. During the stepped withdrawal of remifentanil,
the childrens level of sedation progressively lightened and
this was reflected in the Comfort scale scores (Fig. 2).
EEG data
EEG data were analysed using median power frequency,
spectral edge frequency, and power band ratios.23
 Rigby-Jones et al.

Table 1 Study population. aRemifentanil sedation maintained overnight. bWithdrawn from study due to hypotension. cHypotension on commencement of
remifentanil. Volume given with good effect. dHypotension after onset of remifentanil. Settled spontaneously

Patient Age Weight Sex Procedure Bypass/cross-clamp Remifentanil infusion

number (kg) time (min) duration (min)

1 2 yr 9 months 12.5 Male Left pulmonary artery patch for stenosis 33/0 286
2a 1 month 3.1 Male Left BT shunt No bypass 1238
3b 3 months 4.52 Female BT shunt No bypass 19
4 6 yr 2 months 19.3 Female ASD closure 37/27 190
5 1 yr 4 months 6.2 Male VSD closure 83/54 185
6 9 months 6.1 Female Closure of large ASD and small VSD 58/33 210
7 3 months 4.6 Male Atrial septectomy 25/7 206
8c 1 yr 11 months 10.4 Male Dysplastic pulmonary valve stenosis 42/26 197
9 3 months 3.5 Female Closure of large VSD 52/34 254
10 6 yr 11 months 20.4 Male Subaortic stenosis repair 32/16 177
11 4 yr 1 month 15 Female ASD closure 43/25 225
12 4 yr 7 months 26.6 Female Repair of ASD 59/20 133
13 1 yr 6 months 11.6 Male Glenn shunt 58/0 237
14 9 months 8 Male L modified BT shunt No bypass 219
15 7 yr 10 months 39.8 Female ASD repair 19/28 212
16 1 yr 11 months 17.7 Male VSD closure and pulmonary stenosis repair 58/39 231
(subvalvular)

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17 1 yr 4 months 10.5 Female Multiple VSD repair 29/15 189
18d 1 yr 5 months 8.74 Female Pericardial patch 33/18 132
19 1 yr 10 months 11.7 Female ASD closure 49/27 154
20 1yr 9 months 9.83 Female Closure of sinous venous ASD 50/31 183
21 5 months 3.65 Female VSD and pulmonary valvotomy and PDA ligation 51/28 202
22 5 yr 2 months 18.8 Male Coarctation of the aorta and PDA ligation No bypass/24 150
23 6 yr 21.8 Female Coarctation repair No bypass/14 248
24 3 yr 3 months 13.3 Male Repair of TAPVD 45/30 190
25 7.5 months 7.51 Male VSD and PFO closure 53/36 108
26 9 yr 3 months 30.7 Male MV Re-do 49/29 160

Preliminary exploration revealed no discernible correlation
between these EEG indices and remifentanil blood con-
centrations, remifentanil infusion rate, or Comfort Score.
Hence, these data were not analysed further.
Blood sample analysis
Arterial remifentanil concentrations were closely corre-
lated to the rate of remifentanil infusion (R 20.6,
P,0.001) (Fig. 3). At the commencement of remifentanil
infusion, the median residual fentanyl blood concentration
was 6.4 ng ml21 [minimum 0 (i.e. undetectable),
maximum 15.1, and inter-quartile range 3.1]. The median
midazolam concentration at the beginning of the remifen-
tanil infusion was 87 ng ml21 (minimum 20, maximum
560, and inter-quartile range 111).
Remifentanil concentrations in samples taken at the
point of arousal (n22) showed considerable interpatient
variability. The median concentration at arousal was
3.7 ng ml21 (minimum 1.4, maximum 15.2, and inter-quartile

Fig 2 Mean Comfort scores in children undergoing artificial ventilation

after cardiac surgery. Remifentanil infusion commenced at
0.8 mg kg21 min21 and after a minimum of 1 h was decreased every
20 min in steps of 0.1 mg kg21 min21. Comfort scores were assessed at
steady-state blood concentrations by a trained PICU nurse. Error bars
show 1SD above and below the mean. Note: y-axis truncated.
Fig 3 Mean steady-state arterial concentrations of remifentanil in
children undergoing artificial ventilation after cardiac surgery.
Remifentanil infusion commenced at 0.8 mg kg21 min21 and after a
minimum of 1 h was decreased by 0.1 mg kg21 min21 every 20 min.
Error bars show 1 SD above and below the mean.

256
 Remifentanil sedation in paediatric intensive care

range 2.6). The arousal blood sample from patient 19 did

not contain detectable quantities of remifentanil. The point
of arousal blood samples from patient 1, in which the
remifentanil concentration was 600% higher than in the
previous sample, and from patient 23, who awoke after
stimulation from nursing staff, were not included in the
summary statistics. Fentanyl concentrations in the arousal
samples ranged from 0 (undetectable, n6) to 7.2 ng ml21
(median 1.7, inter-quartile range 2.15). Midazolam concen-
trations in the arousal samples ranged from 14 to
133 ng ml21 (median 59, inter-quartile range 37).

Pharmacokinetics
Remifentanil pharmacokinetics were best described using a
two-compartment model with all structural parameters allo-
metrically scaled to body weight. Age and CPB were not
supported as model covariates. Interindividual variance was

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modelled in all structural parameters with the exception of
Q (distributional clearance). The typical parameter values
for the final model are given in Table 2. Table 3 shows the
parameter estimates and the 95% confidence intervals for a
standard individual weighing 10.5 kg. Figure 4 shows the
model structure and the rate constants, clearances, and
volume for children representing the minimum, maximum,
and median body weights in our study population.

Model evaluation
Figure 5 shows the best and worst model fits. Figure 6
shows the goodness-of-fit plots. The model predicted remi-
fentanil blood concentrations, based on the typical

Table 2 Typical parameter values of the allometric model. CL, irreversible

systemic clearance from the central compartment; Q, intercompartmental Fig 4 The structure of the final model showing the typical rate constants,
clearance; V1, volume of the central compartment; V2, volume of the clearances, and volume parameters for children representing the
peripheral compartment minimum, maximum, and median body weights in our study population.
Pharmacokinetic parameter Typical value

CL (ml min21) 716*(weight/10.5)0.75

Q (ml min21) 840*(weight/10.5)0.75 pharmacokinetic parameter values, demonstrated a median
V1 (ml) 963*(weight/10.5) prediction error (reflecting model bias) of 26.6% and a
V2 (ml) 1480*(weight/10.5) median absolute prediction error (a measure of model pre-
cision) of 19.2%. The leverage analysis demonstrated that
no one patient had undue influence on the parameter esti-
Table 3 Typical parameter estimates for a standard individual weighing mates. Particular attention was paid to the data sets exclud-
10.5 kg. The 95% confidence intervals are symmetric approximations and
were determined as the final parameter estimate+1.96standard error of the
ing patients 2 and 3, who received significantly longer and
estimate. The coefficient of variation (CV%) was determined, where possible, shorter duration remifentanil infusions, respectively, which
as the typical magnitude of the ETA parameter associated with the may have skewed the population parameter estimates.
pharmacokinetic parameter. NA, not applicable
However, excluding these patients resulted in a ,10%
Parameter Typical value 95% confidence CV% change in the structural model parameter values. The
interval
mean values and the 95% confidence intervals resulting
CL (ml min21) 716 663 769 18.4 from the bootstrap procedure (n712 successful runs)
Q (ml min21) 840 26.6 1650 NA were comparable with the NONMEM estimates from the
V1 (ml) 963 489 1440 35.4 original data set. The mean bootstrap values for the struc-
V2 (ml) 1480 639 2320 63.1
Residual error (1) (ng ml21) 1.4 1.36 2.50 tural model parameters differed from the final NONMEM
model values by less than 8%.

257
 Rigby-Jones et al.

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Fig 5 Best [(A) patient 4] and worst [(B) patient 9] model fits. The
dashed line shows the population model prediction, the solid line shows
the individualized model prediction and the black markers show the
measured remifentanil blood concentrations.
Simulation
Our model was used to calculate typical pharmacokinetic
parameter values for children of different body weights.
For comparison, parameter values were also calculated
Fig 6 Plots showing the observed remifentanil blood concentrations vs
the population model predicted values (A) and the individualized model
predicted values (B).
Table 4 Model comparison. Typical pharmacokinetic parameter values
calculated using three different pharmacokinetic models. Volume of
distribution at steady state (VSS) was determined as the sum of the volume of
the central and peripheral compartments
Model CL (ml kg21 min21) V1 (ml kg21) VSS (ml kg21)

using the pharmacokinetic models developed by Davis and Our model

colleagues11 and Minto and colleagues21 (Table 4). The 3 kg baby 93 92 233
parameter values for all three models were used to simu- 10.5 kg child 68 92 233
27 kg child 54 92 233
late remifentanil blood concentration vs time profiles 40 kg child 49 92 233
(Fig. 7). Compared with our data, the Minto model over- Davis11 model (mean 47 84 235
predicts the remifentanil blood concentration. When weight 27 kg)
Minto21 34 67 256
adjusted for bodyweight, the concentration predicted by weight-proportional
the Davis model is similar to that predicted by our model. model (adults)

As our data are entirely derived from cardiac surgery

Discussion
We have carefully evaluated remifentanil as an adjunct
sedative in paediatric patients after cardiac surgery and
demonstrated that it is effective. Our study population was
small; hence, general comments about the safety of this
technique would be inappropriate. However, the adverse
event profile we observed is similar to that reported by
others.11
patients, their applicability to other paediatric populations
cannot be assumed. In addition, our patients were non-
stationary in various regards; drugs given for anaesthesia and
CPB are only gradually eliminated and although we allowed
a reasonable washout period with at least 1 h at the initial
remifentanil infusion rate, residual effects of anaesthesia
cannot be excluded. Residual fentanyl blood concentrations
were probably sufficiently high in some patients to be

258
 Remifentanil sedation in paediatric intensive care
Fig 7 Predicted arterial blood concentrations for remifentanil using three
pharmacokinetic models. Simulations of a 60-min infusion of
remifentanil at 0.8 mg kg21 min21 were made using our model and that
developed by Davis and colleagues11 and Minto and colleagues.21
contributing to the sedative effect provided by remifentanil
and midazolam.24 In addition, despite a fixed scheme for
midazolam administration, measured midazolam concen-
trations demonstrated substantial interpatient variability.
The degree of sedation achieved by a particular infusion
rate may also be different from other paediatric groups,
both for pharmacokinetic reasons (lower blood concen-
trations achieved in smaller patients) and possibly for
pharmacodynamic reasons.
Several groups have evaluated remifentanil as a sedative
agent in children. Bauman and colleagues25 studied six
sedative-hypnotic and analgesic combinations in spon-
taneously breathing children aged 112 undergoing brief
painful procedures. Bolus doses between 0.53 and
1.1 mg kg21 and infusion rates between 0.1 and 0.2
mg kg21 min21 were administered with the smallest doses
proving most satisfactory. When remifentanil was adminis-
tered alone or in combination with midazolam to children
aged 5 16, undergoing bone marrow aspiration, clinical
conditions were satisfactory without adverse events.
However, the patients only received a single bolus of remi-
fentanil 0.5 or 1 mg kg21 and no infusion.9 When used as
a sole agent for sedation during cardiac catheterization,
remifentanil 0.1 mg kg21 min21 was satisfactory in 23/55
children aged 2 months to 12 yr with the remainder requir-
ing supplemental midazolam or midazolam and keta-
mine.26 Thus, small doses of remifentanil are capable of
producing useful sedation and analgesia in a paediatric
population, although almost all clinical experience is with
children older than those in our investigation.
Experience with remifentanil in ventilated children is
more recent and less extensive. Stoppa and colleagues
studied 18 newborns undergoing mechanical ventilation
who received remifentanil for a mean of 70 h with a mean
remifentanil infusion rate of 0.15 mg kg21 min21. No
other sedative or hypnotic drugs were administered. No
adverse events were observed, and the authors concluded
that remifentanil may be a useful analgesic in neonates.27
When remifentanil was compared with fentanyl in chil-
dren aged 3 16 who required mechanical ventilation after
259
spinal surgery, analgesia was clinically comparable with
faster recovery in those patients receiving remifentanil.
Remifentanil infusion was commenced at 0.1 mg kg21
min21 and titrated, but average doses are not reported.
Three of 11 children received supplementary propofol
with the remainder receiving remifentanil alone.8 The
majority of our patients had undergone CPB and were
likely significantly sicker than those described earlier. In
addition, they were receiving their remifentanil infusions
after a substantial dose of fentanyl which may have altered
subsequent opioid sensitivity.
Remifentanil pharmacokinetics after bolus adminis-
tration have been previously described by Davis and col-
leagues11 in cardiac surgery paediatric patients and by
Ross and colleagues28 in children undergoing elective
surgery (including cardiac) and diagnostic procedures. Our
study is the first description of remifentanil pharmaco-
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kinetics during infusion for paediatric sedation.
The allometric relationship between clearance and body
weight in our model results in clearance values that are
proportionally higher in smaller children. The nature of
this relationship, and the range of parameter values, is in
good agreement with the study conducted by Ross and col-
leagues, in which children of similar ages and body
weights are compared. In contrast to Rosss study of chil-
dren from birth to 18 yr, our data did not support a phar-
macokinetic model in which the distribution volume per
kg was larger in smaller children. This may be due to the
smaller age range in our study. We found that although
models including age and body weight as covariates did
result in a reduction in the 22 log-likelihood value (a
model diagnostic in which a smaller value is generally
indicative of an improved model fit), the standard errors of
the estimates of the pharmacokinetic parameters increased
substantially resulting in model instability. This was likely
due to the collinearity of age and weight in our study
population.
When adjusted for body weight, our typical values for
metabolic clearance, volume of the central compartment
(V1) and the volume of distribution at steady state (VSS)
are within 15% of those reported by Davis and col-
leagues11 and hence, produce similar predicted remifenta-
nil blood concentration vs time profiles (Fig. 7). The
combination of enhanced metabolic clearance and a larger
central compartment volume explains the low remifentanil
blood concentrations predicted by our paediatric model
when compared with Mintos adult model.
Davis and colleagues11 found that remifentanil clearance
increased by 20% after CPB in children but found no sig-
nificant difference in estimates of distribution volume or
half-life. We evaluated CPB as a potential model covariate
based on this finding, and on our previous experience with
propofol, where CPB was found to substantially reduce
postoperative metabolic clearance.22 In addition, differ-
ences in volume loading, capillary leakage, and the use of
ultrafiltration could feasibly have resulted in differences in
 Rigby-Jones et al.
the estimates of distribution volume between bypass and
non-bypass patients. However, we were unable to justify the
incorporation of CPB as a pharmacokinetic model covari-
ate. Our study was not designed to investigate the influence
of CPB and as such, our data were unbalanced (5 of 26 chil-
dren did not undergo CPB). Our study was most likely
underpowered to detect small kinetic differences between
children who underwent CPB and those who did not.
In agreement with previous studies,11 28 our data indicate
low interpatient variability in the remifentanil pharmaco-
kinetic parameter values, particularly for clearance and the
volume of the central compartment (,35%). However, the
interpatient variability in the estimates of the peripheral
volume of distribution (V2) was larger at 63.1%. This may
be a result of cardiac surgery and CPB. Cardiac surgery has
profound systemic effects and cardiac function changes,
generally improving, during the first few hours after
surgery. This may influence drug disposition and elimin-
ation as accumulated fluid is cleared. Koren and col-
leagues29 have shown that estimates of distribution volume
for fentanyl in children undergoing cardiac surgery can
depend on the severity of the haemodynamic disturbance.
Although midazolam and fentanyl blood concentrations
were quantified, the absence of a full dosing history for
these drugs prevented pharmacokinetic modelling.
However, had a full dose history been available, it is unli-
kely that the blood-sampling scheme (designed solely to
characterize remifentanil kinetics) would have produced
reliable parameter estimates for fentanyl or midazolam.
Ethical restrictions in the volume of blood that could be
withdrawn for kinetic sampling prohibited quantification
of remifentanil acid, the major remifentanil metabolite, as
this would have required a second assay. Remifentanil
acid is, however, markedly less potent (1/4600th) than the
parent drug.30 Breen and colleagues31 found no correlation
between remifentanil acid blood concentrations and the
time of offset of analgesic and sedative effects after remi-
fentanil infusion in adults with renal impairment.
In conclusion, remifentanil can provide effective sedation
for children requiring ventilation after cardiac surgery. Dose
requirements are higher than those reported for adults with
significant weight-dependency in the smallest patients.
Acknowledgements
Supported by grants from The Association of Anaesthetists of Great Britain
and Ireland, London, and the British Journal of Anaesthesia, London.
Appendix
Sample preparation
Analytical standards of remifentanil and GR92 559, the
assay internal standard, were provided by GlaxoWellcome
(Stevenage, UK). A midazolam analytical standard was
provided by Roche (Basel, Switzerland). Remifentanil,
260
fentanyl, and midazolam were extracted from whole blood
using a modified liquid liquid extraction technique.13
The blood sample (0.9 ml) was aspirated into a pre-cooled
glass tube containing 20 ml of the internal standard sol-
ution (GR92 559, 2 mg ml21 in 0.01 M HCl), followed by
1 ml of sodium phosphate buffer (1 M, pH 7.4). After
brief mixing by agitation, 5 ml 1-chlorobutane was added.
The sample was then mixed (rotary mixer, 50 rpm) for 15
min before centrifugation (3150g) for 15 min at 48C. The
upper organic layer was transferred to a second pre-cooled
glass tube containing 0.2 ml 0.01 M HCl. The tube was
vortex-mixed for 2 min and then centrifuged as above.
The upper organic layer was aspirated and discarded, and
the lower aqueous phase transferred to a glass autosampler
vial. Aliquots (20 ml) of the concentrated sample extract
were analysed in duplicate using a novel high performance
liquid chromatography method.
Downloaded from http://bja.oxfordjournals.org/ by guest on December 14, 2015
High performance liquid chromatography
The separation of remifentanil, fentanyl, GR92 559, and
midazolam was achieved at room temperature using a Kya
HiQSil C18 3 m [1501.0 mm (i.d.)] column (Kromatek,
Essex, UK) and an AS950 autosampler, 2PU2085 micro-
pumps, a 50 ml mixing tee, and a UV2075 detector, all
supplied by Jasco (UK) Ltd (Essex, UK). The mobile
phases consisted of A: 0.06 M sodium dihydrogen ortho-
phosphate pH 3.60, containing 20% methanol:acetonitrile
(2.5:1, v/v), and B: mobile phase A containing 20%
methanol:acetonitrile (2.5:1, v/v). Mobile phase A (100%)
ran for the first 45 min after sample injection during which
time remifentanil eluted from the column, then mobile
phase B (100%) was use to elute fentanyl, GR92 559, and
midazolam. The flow rate was 0.05 ml min21 and the detec-
tion wavelength was 208 nm.
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