Pediatric Anesthesia ISSN 1155-5645

ORIGINAL ARTICLE

Development of an optimal sampling schedule for children

receiving ketamine for short-term procedural sedation and
analgesia
Catherine M.T. Sherwin1, Chris Stockmann1, Kristin Grimsrud2, David W. Herd3, Brian J. Anderson4
& Michael G. Spigarelli1
1 Division of Clinical Pharmacology, Department of Paediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA
2 Campus Veterinary Services and School of Veterinary Medicine, University of California, Davis, CA, USA
3 Department of Anaesthesiology, University of Auckland, Auckland, New Zealand
4 Paediatric Emergency Department, Mater Children’s Hospital, Brisbane, Australia

Keywords
optimal sampling strategy;
pharmacokinetics; pharmacodynamics;
children
Correspondence
Catherine M.T. Sherwin, PhD, FCP, Division
of Clinical Pharmacology, Department of
Paediatrics, University of Utah School of
Medicine, Salt Lake City, UT 84108, USA
Email: Catherine.Sherwin@hsc.utah.edu
Section Editor: Jerrold Lerman
Accepted 5 July 2014
doi:10.1111/pan.12521
Summary
Background: Intravenous racemic ketamine is commonly administered for
procedural sedation, although few pharmacokinetic studies have been con-
ducted among children. Moreover, an optimal sampling schedule has not
been derived to enable the conduct of pharmacokinetic studies that minimally
inconvenience study participants.
Methods: Concentration-time data were obtained from 57 children who
received 1–1.5 mg
kg1 of racemic ketamine as an intravenous bolus. A pop-
ulation pharmacokinetic analysis was conducted using nonlinear mixed
effects models, and the results were used as inputs to develop a D-optimal
sampling schedule.
Results: The pharmacokinetics of ketamine were described using a two-com-
partment model. The volume of distribution in the central and peripheral
compartments were 20.5 l∙70 kg1 and 220 l∙70 kg1, respectively. The inter-
compartmental clearance and total body clearance were 87.3 and
87.9 l
h1∙70 kg1, respectively. Population parameter variability ranged
from 34% to 98%. Initially, blood samples were drawn on 3–6 occasions
spanning a range of 14–152 min after dosing. Using these data, we deter-
mined that four optimal sampling windows occur at 1–5, 5.5–7.5, 10–20, and
90–180 min after dosing. Monte Carlo simulations indicated that these sam-
pling windows produced precise and unbiased ketamine pharmacokinetic
parameter estimates.
Conclusion: An optimal sampling schedule was developed that allowed
assessment of the pharmacokinetic parameters of ketamine among children
requiring short-term procedural sedation.

a neuro-protective effect for patients with traumatic

Introduction
Ketamine is an N-methyl-D-aspartate (NMDA) antago-
nist and is widely used for sedation, induction, and
maintenance of general anesthesia and analgesia (1).
The benefits of ketamine have been well documented in
special populations. In burn patients, ketamine has been
reported to improve analgesia and reduce the need for
opioids (2); in combat trauma, it has been shown to have
brain injuries (3); and in children, it has been used for
conscious sedation in the intensive care unit and
emergency department (4).
There is a scarcity of pediatric ketamine
pharmacokinetic data available (5–7). Nevertheless,
the use of ketamine in pediatric emergency depart-
ments has increased over the last three decades and
it is now commonly administered intra-operatively

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Pediatric Anesthesia 25 (2015) 211–216
Optimal ketamine sampling schedule
and postoperatively for pain control (8–11). The
primary indications for the use of ketamine in the
pediatric emergency department setting include
fracture reduction, joint relocation, facial laceration
repair, wound care and cleaning, incision and drain-
age of abscesses, foreign body removal, and burn
debridement and dressing (12,13). Despite its frequent
use, ketamine dosing protocols vary widely across
institutions (e.g., single bolus vs multiple dosing,
co-administration with benzodiazepines or an antisi-
alogogue, and the rate of drug administration) (14).
We previously reported significant variability in
measured ketamine concentrations, despite administer-
ing dosages that were normalized per kilogram of body
weight (15). Moreover, the relationship between keta-
mine dose, plasma concentrations, and analgesic effects
is poorly defined in children (7,16). Consequently, we
sought to develop an optimal sampling schedule to
accurately characterize the pharmacokinetics of keta-
mine among a cohort of children requiring short-term
sedation. The primary objective was to provide blood
sampling guidance for future studies.
Methods
Clinical data
Clinical data were taken from a published study (15).
All children who received ketamine sedation at the
Auckland Children’s Hospital Emergency Department
were approached for participation in this study during a
6-month period in 2006. The Regional Ethics Commit-
tee reviewed and approved this study. Parental permis-
sion and assent (when applicable) were obtained before
conducting any study-related procedures. Children
undergoing painful procedures received a bolus dose of
racemic ketamine at 1–1.5 mg
kg1 intravenously. Three
to six venous blood samples were obtained from each
participant over a period of 14–152 min postketamine
administration. Serum concentrations were established
using a validated method that has been previously
described (17).
Development of a population pharmacokinetic model
A population pharmacokinetic model was developed
for ketamine using the nonlinear mixed effects
modelling software NONMEM 7.2 (ICON Development
Solutions, Ellicott City, MD, USA) (18). Parameters
were estimated using the first-order conditional
estimation with interaction (FOCEI) algorithm. The
population parameter variability was ascribed to an
exponential model.
212
C.M.T. Sherwin et al.
Covariate selection was performed using a stepwise
forward addition and backward elimination procedure
that has been described previously (19). Age and
height were examined in the covariate analysis to
assess their influence upon ketamine clearance, the
volume of distribution in the central compartment,
and the volume of distribution in the peripheral com-
partment. The median age of the 57 children included
in the study was 8 (interquartile range [IQR] 5.6–
9.4) years. The median weight of the patients included
in this study was 25.4 (IQR 21.6–40.3) kg. The med-
ian height was 129 (IQR 115.0–142.0) cm. There were
no neonates and an insufficient number of infants
enrolled to evaluate the influence of maturation on
ketamine pharmacokinetics.
Ketamine pharmacokinetic parameter estimates were
standardized for a mean body weight of 70 kg using an
allometric model of the form:
 
Wi PWR
Pi ¼ Pstd  ;
Wstd
where Pi is the pharmacokinetic parameter for the i th
participant, Wi is the weight of the i th participant, and
Pstd is the parameter in a theoretical participant with a
Wstd of 70 kg. This standardization facilitates compari-
sons of pediatric parameter estimates with those
reported for adult subjects. The PWR exponent was
fixed at 0.75 for clearance and 1.0 for the central and
peripheral volumes of distribution (20,21).
The Bayesian information criterion (BIC) and the
objective function value were used to perform model
selection among non-nested and nested models, respec-
tively (18,22,23). Additionally, visual examination of the
diagnostic plots and prediction-corrected visual predic-
tive checks was performed to evaluate the fit of the phar-
macokinetic model to the data.
Identification of optimal sampling times
An optimal sampling schedule was developed using pop-
ulation pharmacokinetic parameter estimates as a priori
values. The selection of optimal sampling points was
established according to the D-optimality algorithm
implemented in the software program ADAPT 5 (24). D-
optimal designs minimize the determinant of the inverse
Fisher information matrix and minimize the overall vari-
ance across all pharmacokinetic parameter estimates
(25). D-optimal design theory explicitly assumes that
there is one true vector for each pharmacokinetic param-
eter, which results in the number of optimal samples
being exactly equal to the number of pharmacokinetic
parameters to be estimated (26). In this study, a two-
compartment model was used, which resulted in a total
© 2014 John Wiley & Sons Ltd
Pediatric Anesthesia 25 (2015) 211–216
C.M.T. Sherwin et al. Optimal ketamine sampling schedule

of four pharmacokinetic parameters. Consequently, four basis for this approach has been well described by Foo
optimal sampling times were identified; however, alterna- and Duffull (28).
tive designs involving the collection of five and six blood
samples were also explored and their results are pre-
Results
sented below.
Ketamine is commonly used in the emergency depart-
Population pharmacokinetic model
ment; consequently, a sampling window of 3 h was used
so as not to result in excessively protracted emergency Serum samples were available from 57 children for a
department visits. The validity of the sampling schedule total of 210 unique specimens. The pharmacokinetic
was evaluated using Monte Carlo techniques in which a parameters of ketamine were described with a two-com-
trial of 57 children with a median weight of 25.4 (IQR partment model (Table 1). A prediction-corrected visual
21.6–40.3) kg was simulated. Individual pharmacoki- predictive check was also performed to ensure that the
netic parameters were developed for this simulated
patient population, which were used to simulate keta-
mine concentrations at each of the optimal sampling
times. A new population model was then developed
based upon the concentrations for these simulated
patients. Individual Bayesian estimates were obtained
for each patient and compared with the original phar-
macokinetic parameters, which facilitated calculation of
the bias and precision of the estimated pharmacokinetic
parameters using the optimal sampling schedule (27).
This procedure was performed 2000 times to obtain
mean (standard deviation [SD]) bias and precision
estimates.

Sampling windows
As clinical and logistical circumstances often make it
challenging to obtain a blood sample at a precisely
defined time, we developed sampling windows around
each of the optimal sampling points to allow for this
design to be applied in future prospective clinical
studies. The sampling windows were derived using
WinPOPT, which allowed us to identify a window of
time in which a nearly optimal blood sample could be
obtained. We specified that each sampling window was
to be constrained in time to achieve 90% efficiency in
pharmacokinetic parameter estimation. The Bayesian
Figure 1 Prediction-corrected visual predictive check of the final
population ketamine model. The increase in ketamine concentrations
observed at approximately 60 min was due to the administration of
an additional dose. The solid gray line indicates the median, and
dashed gray lines indicate the 10th and 90th percentiles of the
observed data, respectively. The solid black line indicates the med-
ian, and dashed black lines indicate the 10th and 90th percentiles of
the simulated data, respectively. Open circles depict the prediction-
corrected observed concentrations. Predictions are aggregated
across all 100 simulated trials.

Table 1 Ketamine population pharmacokinetic parameter and residual error estimates

Bootstrapped 95% % Population parameter %

Parameter Units Estimate confidence interval variability Shrinkage

Pharmacokinetic parameters
CL l h1∙70 kg1 87.3 64.8–111 52.9 9.7
Vcentral l∙70 kg1 20.5 13.4–33.1 97.8 7.4
Q l h1∙70 kg1 220 166–217 60.7 9.0
Vperipheral l∙70 kg1 87.7 57.9–123 34.1 30.4
Residual error
Additive – 0 FIXED – – –
Proportional % 21.2 16.2–25.8 – 21.2

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Pediatric Anesthesia 25 (2015) 211–216
Optimal ketamine sampling schedule
model predictions matched the measured ketamine con-
centration-time course (Figure 1). After accounting for
the allometric scaling of weight, neither of the covariates
tested exerted a significant influence upon ketamine
pharmacokinetic parameter estimates.
Optimal sampling times
Use of the D-optimality algorithm yielded an optimal
sampling schedule with blood draws at 1, 5.5, 16, and
180 min postdose (Figure 2). By collecting a single
sample at each of these time points, the coefficient of
variation (%CV) for each of the pharmacokinetic
parameters is expected to range from 13% to 39%.
Alternative designs involving the collection of five or six
samples and their respective %CV and optimal sampling
times are presented in Table 2.
The predictive performance of the optimal sampling
schedule involving the collection of four blood samples
was evaluated using Monte Carlo simulation techniques
(n = 2000). The bias and precision of the four ketamine
pharmacokinetic parameters are featured in Table 3.
The estimates obtained for all four pharmacokinetic
parameters had bias <11% and precision within 41%.
Figure 2 Optimal sampling strategy to accurately estimate the pop-
ulation pharmacokinetics of ketamine among children requiring short-
term sedation in the emergency department.
214
C.M.T. Sherwin et al.
Sampling times in children are not always possible at
precisely defined optimal time points because of the
child’s clinical instability, noncompliance, or coincident
blood sampling for other medical reasons.
Consequently, sampling windows were developed using
Bayesian methods to identify windows of opportunity
around each sampling point to achieve 90% precision in
estimating ketamine pharmacokinetic parameters. The
four samples may be taken at 1–5, 5.5–7.5, 10–20, and
90–180 min postdose. It must be noted that the exact
times must be recorded when each of the samples are
obtained to facilitate accurate population pharmacoki-
netic parameter estimation.
Discussion
This study establishes an optimal sampling schedule for
the assessment of ketamine pharmacokinetic parameters
in children. Several techniques and software platforms
have been developed to identify the most informative
times to obtain serial pharmacokinetic samples accord-
ing to optimal sampling theories (29–31). In this study,
we used a Bayesian approach that estimates the full
pharmacokinetic profile for each individual using a lim-
ited number of ketamine plasma concentration measure-
ments over a period of 3 h (32). Four samples collected
at 1–5, 5.5–7.5, 10–20, and 90–180 min were found to
adequately characterize ketamine pharmacokinetic
parameters with no significant bias and precision rang-
ing from 8% to 41%.
Controlling pain and minimizing stressful proce-
dures is vitally important in critically ill pediatric
patients. Ketamine is frequently used in the emer-
gency department to provide short-term sedation and
analgesia for children undergoing minor surgical
procedures (14). Successful procedural sedation is a
direct function of administering the optimal dose at
the ideal dosing interval (33). However, rational
dosing of medications in pediatric patients remains
an unmet clinical need. Our limited understanding of
ketamine pharmacokinetics in children has historically
resulted in initial dosing regimens that vary greatly
(8,10,34). The availability of several large case series
has helped improve clinical dosing decisions with
regard to patient safety, although these were not
designed to enhance therapeutic effectiveness at the
level of the individual patient (35,36). In this study, we
adopted a Bayesian approach to allow for the identifi-
cation of the most ‘information-rich’ areas of the drug
concentration-time curve using the least number of
blood samples (27,37). Using Monte Carlo simulation,
these sampling times were found to be unbiased and
reasonably precise, which suggests that they may be
© 2014 John Wiley & Sons Ltd
Pediatric Anesthesia 25 (2015) 211–216
C.M.T. Sherwin et al. Optimal ketamine sampling schedule

Table 2 Ketamine optimal sampling designs involving the collection of 4, 5, and 6 blood samples

Expected % coefficient
Pharmacokinetic parameter Parameter estimate of variation

4 sample design
Total body clearance (CL) 87.9 l
h1∙70 kg1 13.2
Volume of distribution in the central compartment (Vcentral) 20.5 l∙70 kg1 20.0
Intercompartmental clearance (Q) 87.3 l
h1∙70 kg1 39.3
Volume of distribution in the peripheral compartment (Vperipheral) 220 l∙70 kg1 18.4
Optimal sampling times 1, 5.5, 16, and 180 min
5 sample design
Total body clearance (CL) 87.9 l
h1∙70 kg1 10.1
Volume of distribution in the central compartment (Vcentral) 20.5 l∙70 kg1 20.0
Intercompartmental clearance (Q) 87.3 l
h1∙70 kg1 37.7
Volume of distribution in the peripheral compartment (Vperipheral) 220 l∙70 kg1 15.2
Optimal sampling times 1, 5.5, 16 (n = 2), and 180 min
6 sample design
Total body clearance (CL) 87.9 l
h1∙70 kg1 8.7
Volume of distribution in the central compartment (Vcentral) 20.5 l∙70 kg1 17.9
Intercompartmental clearance (Q) 87.3 l
h1∙70 kg1 37.1
Volume of distribution in the peripheral compartment (Vperipheral) 220 l∙70 kg1 14.9
Optimal sampling times 1, 5.5, 16 (n = 3), and 180 min

Table 3 Bias and precision of ketamine pharmacokinetics deter-
mined through Monte Carlo simulation
Mean % Bias Mean % Precision
Parameter (SD) (SD)
CL 0.8 (10.2) 8.2 (6.1)
Vcentral 10.5 (61.3) 39.1 (48.2)
Q 1.1 (16.5) 13.0 (10.2)
Vperipheral 10.6 (55.3) 40.9 (38.5)
used prospectively to clearly define the population
pharmacokinetics of ketamine among children undergo-
ing short-term sedation in the emergency department
using a limited number of samples.
Pharmacokinetic and pharmacodynamic studies are
difficult to perform in children due to ethical and
logistical constraints, including the limited number and
quantity of specimens, as well as the extent and inva-
siveness of study-related interventions that are not part
of routine clinical care (38). To overcome some of
these challenges, we have developed a D-optimal phar-
macokinetic study design. Optimal sampling theory
requires a priori knowledge of the pharmacokinetic
parameters to be estimated. In this study, we devel-
oped a population pharmacokinetic model using data
from 57 children who each contributed 3–6 ketamine
concentrations. These population pharmacokinetic
parameter estimates were then incorporated within a
Bayesian model to estimate individual pharmacokinetic
parameters. This approach enhances the accuracy and
applicability of estimates obtained from datasets that
do not completely describe the entire pharmacokinetic
profile of the drug (39). However, incomplete data,
model misspecification, and high population parameter
variability may decrease the sensitivity of our optimal
sampling strategy.
Conclusion
The data generated from this study will provide a
framework for improving study designs of forthcom-
ing pediatric ketamine studies and minimize sample
collection in this vulnerable patient population.
Future studies to characterize the pharmacokinetics
and pharmacodynamics of ketamine in special popu-
lations are warranted to optimize dosing regimens
hereby improving patient care and minimizing the
incidence of adverse events.
Acknowledgments
Financial support was provided by research grants from
the Society for Paediatric Anaesthesia of New Zealand
and Australia (SPANZA). Dr. Herd was supported by
the Royal Australasian College of Physicians, the Mau-
rice and Phyllis Paykel Trust, and the Joan Mary Rey-
nolds Fellowship.
Ethical approval
This study was approved by the Regional Ethics Com-
mittee and written informed consent was obtained from

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Pediatric Anesthesia 25 (2015) 211–216
Optimal ketamine sampling schedule
parents/guardians. Additionally, assent was obtained
from children 6 years of age and older.
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