Perioperative Medicine

ABSTRACT
Background: Numerous pharmacokinetic models have been published
aiming at more accurate and safer dosing of dexmedetomidine. The vast

Dexmedetomidine majority of the developed models underpredict the measured plasma concen-
trations with respect to the target concentration, especially at plasma concen-

Clearance Decreases with

trations higher than those used in the original studies. The aim of this article
was to develop a dexmedetomidine pharmacokinetic model in healthy adults

Increasing Drug Exposure:

emphasizing linear versus nonlinear kinetics.
Methods: The data of two previously published clinical trials with step-

Implications for Current wise increasing dexmedetomidine target-controlled infusion were pooled to
build a pharmacokinetic model using the NONMEM software package (ICON

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Dosing Regimens and Development Solutions, USA). Data from 48 healthy subjects, included in a
stratified manner, were utilized to build the model.

Target-controlled Infusion Results: A three-compartment mamillary model with nonlinear elimination

from the central compartment was superior to a model assuming linear phar-

Models Assuming Linear macokinetics. Covariates included in the final model were age, sex, and total
body weight. Cardiac output did not explain between-subject or within-subject

Pharmacokinetics variability in dexmedetomidine clearance. The results of a simulation study

Ricardo Alvarez-Jimenez, M.D., Ph.D.,
Maud A. S. Weerink, M.D., Laura N. Hannivoort, M.D., Ph.D.,
Hong Su, Pharm.D., Michel M. R. F. Struys, M.D., Ph.D., F.R.C.A.,
Stephan A. Loer, M.D., Ph.D., Pieter J. Colin, Pharm.D., Ph.D.
Anesthesiology 2022; 136:279–92
EDITOR’S PERSPECTIVE
What We Already Know about This Topic
• Dexmedetomidine pharmacokinetic models underpredict the mea-
sured plasma target-controlled infusion concentrations that are
higher than those used in the model validation studies
• The elimination clearance of high hepatic extraction ratio drugs like
dexmedetomidine is determined by liver blood flow and not enzyme
activity
based on the final model showed that at concentrations up to 2 ng · ml–1,
the predicted dexmedetomidine plasma concentrations were similar between
the currently available Hannivoort model assuming linear pharmacokinetics
and the nonlinear model developed in this study. At higher simulated plasma
concentrations, exposure increased nonlinearly with target concentration due
to the decreasing dexmedetomidine clearance with increasing plasma con-
centrations. Simulations also show that currently approved dosing regimens
in the intensive care unit may potentially lead to higher-than-expected dexme-
detomidine plasma concentrations.
Conclusions: This study developed a nonlinear three-compartment phar-
macokinetic model that accurately described dexmedetomidine plasma
concentrations. Dexmedetomidine may be safely administered up to tar-
get-controlled infusion targets under 2 ng · ml–1 using the Hannivoort model,
which assumed linear pharmacokinetics. Consideration should be taken
during long-term administration and during an initial loading dose when fol-
lowing the dosing strategies of the current guidelines.
(ANESTHESIOLOGY 2022; 136:279–92)

What This Article Tells Us That Is New

• The data of 48 subjects from two published pharmacokinetic stud-
ies were pooled to build a three-compartment pharmacokinetic model
with nonlinear elimination clearance that successfully predicted plasma
dexmedetomidine concentrations over a wide concentration range
• Cardiac output did not explain between-subject or within-subject
variability in dexmedetomidine elimination clearance
• Dexmedetomidine elimination clearance may decrease with
increasing plasma concentrations because it alters the liver blood
flow–to–cardiac output ratio in a concentration-dependent manner
D
exmedetomidine is widely known for its anxiolytic,
sedative, and analgesic effects due to its central α2-
adrenergic agonistic properties, which provide a unique
arousable sedation profile with minimal ventilatory effects
when used in therapeutic ranges.1,2 Nowadays, dexmedeto-
midine is approved for short-term use in mechanically ven-
tilated patients admitted to the intensive care unit (ICU) and
for periprocedural sedation. A considerable amount of effort

This article is featured in “This Month in Anesthesiology,” page A1. This article is accompanied by an editorial on p. 258. Supplemental Digital Content is available for this article.
Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this
article on the Journal’s Web site (www.anesthesiology.org). This article has a visual abstract available in the online version.
Submitted for publication October 16, 2020. Accepted for publication October 4, 2021. Published online first on December 1, 2021. From the Department of Anesthesiology, Amsterdam
University Medical Center, Amsterdam, The Netherlands (R.A.-J., S.A.L.); the Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The
Netherlands (M.A.S.W., L.N.H., H.S., M.M.R.F.S., P.J.C.); and the Department of Basic and Applied Medical Sciences, Ghent University, Ghent, Belgium (M.M.R.F.S.).
Copyright © 2021, the American Society of Anesthesiologists. All Rights Reserved. Anesthesiology 2022; 136:279–92. DOI: 10.1097/ALN.0000000000004049

ANESTHESIOLOGY, V 136 • NO 2 February 2022 279

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<zdoi;. DOI: 10.1097/ALN.0000000000004049>
 PERIOPERATIVE MEDICINE
has been invested to elicit a deeper understanding and char-
acterization of dexmedetomidine’s pharmacology among
all ages and clinical conditions. As a result, numerous and
heterogeneous pharmacokinetic (and pharmacodynamic)
models have been published.These models aim to develop a
more accurate and safer dosing regime that permits a faster
onset of the desired effects while diminishing the risk for
undesirable cardiovascular effects.3,4 Unfortunately, the vast
majority of the developed models underpredict the mea-
sured plasma concentrations with respect to the target con-
centration, especially at higher plasma concentrations than
those originally used in the validation studies. For exam-
ple, Hsu et al.5 using the model developed by Dyck et al.,6
Snapir et al.7 using the model developed by Talke et al.,8 and
Weerink et al.9 using the model developed by Hannivoort
et al.10 underpredicted the measured plasma concentra-
tions at higher targets. All aforementioned models include
a two- or three-compartment mammillary model struc-
ture with first-order kinetics. Dutta et al.11 have suggested
that dexmedetomidine’s pharmacokinetic profile exhibited
nonlinear kinetics. During a recent dexmedetomidine trial
conducted at our hospital, we noticed that there was bias in
the predictions differing from the target-controlled infusion
model for plasma concentrations above the 3.0 ng · ml–1
target-controlled infusion targets,9 indicating a potential
nonlinear increase in exposure with increasing dexmedeto-
midine target concentrations. The aim of the article was to
investigate whether dexmedetomidine clearance is nonlin-
ear, to establish whether between-subject or within-subject
differences in cardiac output explain this apparent nonlin-
earity, to determine the clinical importance of this phe-
nomenon when following the current recommended dose
regimen guidelines, and to establish the potential impact
on the use of the currently available (linear) Hannivoort
dexmedetomidine model.10
Materials and Methods
Study Design and Data Collection
The data of two previously published clinical trials,9,10
conducted in healthy subjects at the Department of
Anesthesiology at the University Medical Center
Groningen (Groningen, The Netherlands) were pooled
to build a pharmacokinetic model. Both trials were con-
ducted in accordance with the Declaration of Helsinki
and in compliance with good clinical practice and the
applicable regulatory requirements. Both trials explored
the effects of increasing target concentrations of dex-
medetomidine stepwise using target-controlled infusion.
Ethical approval was obtained from an independent medi-
cal ethics review committee (Medisch Ethische Toetsings
Commissie) by the Association for the Evaluation of
Ethics in Biomedical Research (Stichting Beoordeling
Ethiek Biomedisch Onderzoek, Assen, The Netherlands).
Both studies were registered in the ClinicalTrials.gov
280 Anesthesiology 2022; 136:279–92
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database (NCT03143972 and NCT01879865). Written
informed consent was obtained before performing a
standard medical screening, which included a thorough
medical history and a physical examination. Exclusion cri-
teria included a body mass index greater than 30 kg ∙ m–2
or less than 18 kg ∙ m–2, an age less than 18 yr or above
70 yr, pregnancy, or currently breastfeeding. Alcohol
consumption, smoking, and use of concomitant (ille-
gal) drugs were not allowed during study participation.
Inclusion was stratified according to age and sex in both
studies. Subjects were in fasting conditions during each
study period.
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Trial by Hannivoort et al.
For the first study, 18 subjects were included. For a thor-
ough description of the study demographics, data col-
lection, and analytic methods, please refer to Hannivoort
et al.10 In short, during the trial, an initial 20-s 6-µg ∙ kg–1 ∙ h–1
infusion was started. Ten minutes after the start of this
infusion, a dexmedetomidine target-controlled infusion
was started with stepwise increasing targets of 1, 2, 3, 4, 6,
and 8 ng · ml–1. Each target was maintained for 30 min
using the model developed by Dyck et al.6 Arterial blood
samples were obtained at baseline, 2 min after the initial
20-s infusion, before each increase in target concentration
(at 10 min and every 30 min thereafter), during the target-
controlled infusion administration period, and at 0, 2, 5, 10,
20, 60, 120, and 300 min during the postinfusion period.To
avoid hypertension, the infusion rate was limited to 6 µg ∙
kg–1 ∙ h–1 for the first three infusion steps and was increased
to 10 µg ∙ kg–1 ∙ h–1 for the two highest target-controlled
infusion targets of 6 and 8 ng · ml–1. The upper and lower
limits of quantification for the analytical method were 0.02
and 20 ng · ml–1.
Trial by Weerink et al.
In the second study, 30 subjects were included. For a thor-
ough description of the study demographics, data collec-
tion, and analytic methods, please refer to Weerink et al.9
Only data from the first period (dexmedetomidine alone
and not in combination with remifentanil) were used for
the current analysis. Target-controlled infusion was started
with stepwise increasing targets of 1, 3, 4, 5, and 8 ng · ml–1
every 40 to 50 min using the previously developed dex-
medetomidine model by Hannivoort et al.10 Arterial blood
samples were drawn at baseline and at pseudo-steady state
before changing the target concentration. Once the infu-
sion was stopped, dexmedetomidine samples were drawn at
2, 5, 10, 20, 60, 120, 300, and 420 min. Dexmedetomidine
infusion was limited to 6 µg ∙ kg–1 ∙ h–1 for the first three
infusion steps and was increased to 10 µg ∙ kg–1 ∙ h–1 for the
two highest targets of 5 and 8 ng · ml–1. The protocol was,
however, amended to lower the highest dexmedetomidine
target from 8 to 6 ng · ml–1 due to safety concerns. The
Alvarez-Jimenez et al.

upper and lower limits of quantification for the analytical
method were 0.05 and 20 ng · ml–1.
Study Drug Administration and Data Collection
Dexmedetomidine administration was conducted using
RUGLOOP II software (Demed, Belgium) using a syringe
pump with an Orchestra module DPS (Orchestra Base A,
Fresenius Kabi, Germany); the software also recorded all
vital parameters, pump infusion rates, and eventual case
report form annotations during the execution of the clini-
cal trials. Continuous cardiac output was measured through
a FloTrac sensor connected to a Vigileo monitor (both from
Edwards Lifesciences, USA) in the trial by Hannivoort et
al.10 and through a hemodynamic monitor (EV1000 moni-
tor with FloTrac sensor; Edwards Lifesciences, USA) in the
trial by Weerink et al.9
Pharmacokinetic Model Development
Statistical Analysis
Data set creation, goodness of fit plots, and simulations were
performed using R statistical software (R Foundation for
Statistical Computing, 2018; version 3.5.0). Nonlinear mixed
effects modeling was conducted using the NONMEM
(version 7.3.0) software package (ICON Development
Solutions, USA). In the first trial by Hannivoort et al.,10
there were concentrations below the limit of quantification
limit.Values below the limit of quantification were handled
using the M3 method according to Ahn et al.12
Model Building and Parameter Estimation
The set of differential equations were solved using a sec-
ond-order approximation method (LAPLACE option)
using the ADVAN13 subroutine. The a priori model
assumed weight-based allometric scaling on all pharmaco-
kinetic parameters using a fixed exponent of 1 on volume
of distribution terms and an exponent of 0.75 on clearance
terms.13 Interindividual variability was incorporated using a
log-normal distribution. Residual variability was modeled
using a proportional and additive error model. Candidate
models were compared using the Akaike information cri-
terion, and the model with the lowest Akaike criterion was
taken forward. Covariates were screened by exploring plots
of random effects versus covariates and were included in the
model if inclusion resulted in a decrease in the Akaike cri-
terion. The covariates that were tested for inclusion in the
model were age (yr), total body weight (kg), height (cm),
and sex. The derived parameters body surface area, body
mass index, and lean body mass were also tested.
Testing Cardiac Output as a Covariate on
Dexmedetomidine Clearance
The influence of cardiac output on clearance was tested
according to equation 1. This equation allows simultaneous
Alvarez-Jimenez et al. Anesthesiology 2022; 136:279–92
Copyright © 2021, the American Society of Anesthesiologists. All Rights Reserved. Unauthorized reproduction of this article is prohibited.
Dexmedetomidine Elicits Nonlinear Kinetics
estimation of the effect of a covariate on between- and within-
subject variability on a pharmacokinetic parameter.14
FCO = e ( BSV )
θ ⋅ (CObaseline − 6.6) +θWSV ⋅ (CO −CObaseline )
(1)

In equation 1, FCO represents the effect of cardiac output (CO)
on dexmedetomidine clearance. In the model, FCO was a pro-
portional factor on dexmedetomidine clearance.The parame-
ters θBSV and θWSV are estimated to quantify the influence on
dexmedetomidine clearance of between-subject variability in
baseline cardiac output (CObaseline) compared to the median
in the population (6.6 l ∙ min–1) and within-subject longitu-
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dinal changes from baseline cardiac output. Cardiac output
was included in the data set as a time-varying covariate with
backward constant interpolation between observations.
Model Evaluation
In-sample predictive performance variability was evalu-
ated according to Varvel et al.15 using the median perfor-
mance error and the median absolute performance error as
described in equation 2.
C p observed − C p predicted
PE = ⋅ 100% (2)
C p predicted

where CP indicates the dexmedetomidine plasma concen-
tration, and PE indicates the performance error.
Model precision and parameter identifiability along with
the variance of the parameters random effects were used
to numerically assess the models. Goodness of fit plots and
visual predictive check plots were used to visually assess the
model performance.The visual predictive checks were con-
structed according to Bergstrand et al.16 and were based on
1,000 simulations. To graphically represent the difference
in performance between the linear Hannivoort model and
our final nonlinear model, individual level visual predic-
tive checks were conducted for six subjects from our data
set that had the highest median performance error values
according to the linear Hannivoort model.
Simulations
Visual predictive check simulations were based on a sample
of 1,000 virtual subjects with characteristics randomly sam-
pled from the multivariate distribution of observed patient
characteristics from our study. Plasma target-controlled infu-
sion simulations were based on the Hannivoort model that
assumes first-order pharmacokinetics, taking into account
the maximal recommended infusion rate of 6 µg ∙ kg–1 ∙ h–1 .
Effect-site target-controlled infusion simulations were based
on the ke0 from the dexmedetomidine pharmacokinetic–
pharmacodynamic model for the Modified Observer’s
Assessment of Alertness and Sedation (MOAA/S) score17
(ke0 = 4.85 ∙ 10–2 min–1) and were based on the PKPD
Tools for Excel package.18 The ICU simulations consisted
281
 PERIOPERATIVE MEDICINE

of a loading dose of 1 µg ∙ kg–1 over 10 min followed by Nonlinear dexmedetomidine clearance was tested in the
a constant rate of 0.7 μg ∙ kg–1 ∙ h–1 for 1 h and, alterna- model using equation 3:
tively, followed by the maximum recommended constant
rate infusion of 1.4 µg ∙ kg–1 ∙ h–1 over 24 h according to  I MAX ⋅ C p γ 
CL = CL0 ⋅ 1 − γ  (3)
the European Medicinal Agency Summary of Medicinal
Product Characteristics19 for sedation in the ICU.  ( γ
C p + C 50 ) 

where the clearance at a particular plasma concentration
Results
ranges between CL0 and CL0 ∙ (1 – IMAX) depending on
Analysis Data Set the plasma concentration of dexmedetomidine (Cp). C50
determines the concentration at which 50% of inhibition
The final analysis data set included 48 subjects, 18 subjects takes place, and the exponent (γ) determines the steepness
from the trial by Hannivoort et al.,10 and 30 were from

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of the relationship. IMAX represents the theoretical maxi-
the trial by Weerink et al.9 From the trial by Hannivoort mum inhibitory effect at which dexmedetomidine clear-
et al.,10 two sessions, separated by a washout, were included. ance decreases depending on the plasma concentration. In
From a total of 762 observations, 29 plasma concentration the tested models, IMAX was fixed to 1 (i.e., dexmedetomi-
were below the lower limit of quantification in the trial dine clearance decrease to 0 at very high concentrations) to
by Hannivoort et al.10 There were no samples below the avoid numerical difficulties with the parameter estimation.
lower limit of quantification in the trial by Weerink et al.9 Inclusion of equation 3 in the three-compartment model
Dexmedetomidine concentrations ranged from 0.02 to resulted in a significant decrease in the Akaike criterion of
14.4 ng · ml–1. A stratified inclusion resulted in a balanced 169 points. Figure 1 depicts the post hoc clearance for all
population: 24 subjects were male, and 24 subjects were subjects in the data set as a function of the dexmedetomi-
female. The mean age was 42.2 yr (range, 18 to 70 yr). The dine plasma concentration. Supplemental Digital Content
mean total body weight was 74.8 kg (SD, 13.3 kg; and range, figure S3 (http://links.lww.com/ALN/C743) shows that
49 to 110 kg), and height was 176.2 cm (SD, 10.7 cm; and this nonlinear kinetic model adequately described both
range, 155 to 203 cm). In total, 17 subjects were between 18 data sets. Interoccasion variability was tested on all phar-
and 34 yr old, 15 were between 35 and 50 yr old, and 16 macokinetic parameters but did not result in a decrease in
were between 51 and 70 yr old . Cardiac output measure- the model Akaike criterion. The additive error term in the
ments were available at a resolution of 1 measurement every model for the trial by Weerink et al.9 was negligible and was
10 s, resulting in a median of 728 (range, 194 to 1,375) car- therefore removed.
diac output measurements per subject included in the data
set. Figure S1 of Supplemental Digital Content (http:// Covariate Analysis
links.lww.com/ALN/C743) shows the measured cardiac
output against the measured dexmedetomidine plasma Covariates were tested after accepting the model with non-
concentrations for all subjects included in the analysis. linear elimination and once interindividual variability was
incorporated. In our final model, as shown in equations 4
to 8 and table 2, the volumes of distribution (V1,V2, and V3)
Structural Model Development
scaled linearly with FSIZE, the intercompartment clearance
Linear versus Nonlinear Elimination Kinetics (Q1 and Q2) scaled with size according to an exponent
of 0.75, and CL0 scaled with FSIZE according to an expo-
A three-compartment mamillary model with linear phar- nent of 0.75 and decreased with increasing age as function
macokinetics from the central compartment was used as of FAGE.
the starting point for the model development. This first
model showed considerable bias in the highest predicted  WGT
concentrations when compared to the measured observa-  Male =
70 (4)
tions (Supplemental Digital Content fig. S2, http://links. FSIZE 
WGT
lww.com/ALN/C743). Although the linear pharmacoki- Female = ⋅ (1 + θSEX ~ FSIZE )
 70 
netic model adequately described the data from the trial by
Hannivoort et al.10 (the data set on which this model was
FAGE = e (
−θ AGE ~CL 0 ⋅ ( AGE − 35))
developed, upper panel in Supplemental Digital Content (5)

fig. S2, http://links.lww.com/ALN/C743), it did not ade-
quately describe the observations from the trial by Weerink V = θV · FSIZE  (6)
et al.9 (lower panel in Supplemental Digital Content fig. S2,
http://links.lww.com/ALN/C743). Subsequent modifica- CL0 = θCL 0 · FSIZE 0.75 ⋅ FAGE  (7)
tions to this starting model are summarized in the model
development log as presented in table 1. Q = θQ ⋅ FSIZE 0.75 (8)


282 Anesthesiology 2022; 136:279–92 Alvarez-Jimenez et al.

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 Dexmedetomidine Elicits Nonlinear Kinetics

Table 1. Dexmedetomidine Model Development Log

Akaike Change in Reference

Model Characteristics Criterion Akaike Criterion Model

1 Three-compartment, clearance with linear kinetics –663.1

2 Three-compartment, clearance with nonlinear kinetics –831.8 –168.7 Model 1
3 Three-compartment, clearance with nonlinear kinetics and sex on FSize –842.8 –11.0 Model 2
4 Final model: three-compartment, clearance with nonlinear kinetics, sex on FSize, and age on clearance –849.8 –7.00 Model 3

The estimates of the final model can be found in table 2. Akaike criterion = –11). In addition, age was a significant
Figure 2 presents the goodness of fit plots of the final covariate on CL0 (change in Akaike criterion = –7), and

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model, which showed no clear systematic trend or bias, con-
firming the adequacy of the model to describe the concen-
tration-time profiles of dexmedetomidine. The final (log-)
likelihood profiles can be found in Supplemental Digital
Content figure S4 (http://links.lww.com/ALN/C743).
Supplemental Digital Content figure S5 (http://links.lww.
com/ALN/C743) depicts the prediction- and variance-cor-
rected visual predictive check for the final model. The
parameter uncertainty was considered acceptable and ranged
between 4 and 32.7% for the fixed effects and 30.5 to 40.8%
for the random effects.The final model had a median absolute
performance error of 21.7% and a median performance error
of –2.3%. Figure 3 presents the individual-level visual predic-
tive check for the linear pharmacokinetic model (blue lower
panels) and the nonlinear pharmacokinetic model (gray upper
panels) for six subjects from our data set. In this graph, it is
clear that the highest concentrations are not contained in the
95% prediction interval for the linear pharmacokinetic model.
We found that females had a higher estimated FSIZE by
a factor of 1.18 compared to males (equation 4; change in
CL0 decreased with age as shown in equation 5. On aver-
age, for every 10 yr of age, the clearance decreased by 5.1%.
There were no significant correlations between C50 and the
tested covariates.
We found that cardiac output did not explain
between-subject or within-subject variability in dex-
medetomidine clearance. Implementation of equation 1
in the model did not significantly decrease the objec-
tive function value (change in Akaike criterion = +1.2; P
value for likelihood ratio test = 0.25 for 2 degrees of free-
dom). The estimated parameters for θBSV and θWSV were
0.0211 and 0.0037 and indicate that the estimated effect
of cardiac output on clearance is negligible. According
to equation 1, these estimates denote (1) that an individ-
ual with a cardiac output that is 50% of the population
median (6.6 l ∙ min–1) has a dexmedetomidine clearance
that is 6.7% lower compared to the typical clearance and
(2) that a relative change from baseline cardiac output
of 50% is associated with a 1.2% decrease in dexmede-
tomidine clearance. Prediction-variance–corrected visual

1.5
Post hoc clearance (L/min)

1.0

0.5

0.0
0 5 10 15
Plasma concentration (ng/mL)

Fig. 1. Post hoc clearance versus plasma concentrations. The gray-shaded area denotes the 95% prediction interval according to the final
model with nonlinear elimination. The red line denotes the predicted median values at every plasma concentration of the model. The gray
lines around the mean depict the post hoc predicted clearance estimates against the plasma concentrations for all subjects included in our
analysis.

Alvarez-Jimenez et al. Anesthesiology 2022; 136:279–92 283

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 PERIOPERATIVE MEDICINE

Table 2. Dexmedetomidine Final Pharmacokinetic Parameters

Pharmacokinetic Parameter Estimate (Relative Standard Error %) [95% CI]*

FSIZE  WGT
 Male =
70

Female = WGT ⋅(1 + θ
 SEX ~FSIZE )
70

θSEX~FSIZE 1.80 ∙ 10–1 (26.2) [0.91 ∙ 10–1 to 2.76 ∙ 10–1]

FAGE
e
( −θ AGE ~CL ⋅ ( AGE − 35))
θAGE~CL 5.19 ∙ 10–3 (32.7) [1.90 ∙ 10–3 to 8.57 ∙ 10–3]

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V1 (l) θV 1 ⋅ FSIZE
θV1 1.87 (13.8) [1.38 to 2.40]
V2 (l) θV 2 ⋅ FSIZE
θV2 17.8 (9.11) [15.3 to 21.7]
V3 (l) θV 3 ⋅ FSIZE
θV3 67.4 (3.33) [63.5 to 72.3]
CL0 (l ∙ min–1)
θCL 0 ⋅ FSIZE 0.75 ⋅ FAGE
θCL0 7.99 ∙ 10–1 (5.28) [7.25 ∙ 10–1 to 8.91 ∙ 10–1]
Q2 (l ∙ min–1)
θQ 2 ⋅ FSIZE 0.75
θQ2 2.97 (11.2) [2.45 to 3.77]
Q3 (l ∙ min–1)
θQ 3 ⋅ FSIZE 0.75
θQ3 7.54 ∙ 10–1 (4.02) [6.92 ∙ 10–1 to 8.10 ∙ 10–1]
C50 (ng ∙ ml–1) 5.75 (15.0) [4.27 to 7.64]
γ 1.34 (11.4) [1.08 to 1.67]
Between-subject variability (coefficient of variation %)†
V2 39.9 (35.1) [28.3 to 54.8]
CL0 15.1 (32.8) [11.0 to 20.4]
C50 57.9 (30.5) [44.2 to 77.4]
Residual unexplained variability (SD)‡
Proportional error – Hannivoort study 1.62 ∙ 10–1 (4.31) [1.50 ∙ 10–1 to 1.78 ∙ 10–1]
Proportional error – Weerink study 1.44 ∙ 10–1 (4.43) [1.33 ∙ 10–1 to 1.58 ∙ 10–1]
Additive error – Hannivoort study 2.84 ∙ 10–2 (12.5) [2.25 ∙ 10–2 to 3.65 ∙ 10–2]

*Relative standard error (%) is calculated from the log-likelihood profiles. †Coefficient of variation (%) is calculated according to ω 2 * 100%, where ω2 is the estimated variance in
the NONMEM software package (version 7.3.0; ICON Development Solutions, USA). ‡SD is calculated as the square root of the estimated variance in NONMEM.
Age, subject age (yr); C50, dexmedetomidine concentration where the clearance is half-maximal; CL0, clearance; FAGE, factor to account for age-related changes in pharmacokinetic
parameters; FSIZE, factor to account for size-related changes in pharmacokinetic parameters; Q2, distributional clearance between the central and the fast peripheral compartment; Q3,
distributional clearance between the central and the slow peripheral compartment; V1, volume of distribution of the central compartment; V2, volume of distribution of the fast peripheral
compartment; V3, volume of distribution of the slow peripheral compartment; WGT, subject weight (kg); γ, steepness of the relationship between the dexmedetomidine concentration
and resulting decrease in dexmedetomidine clearance.

predictive checks stratified by covariate for total body
weight (Supplemental Digital Content fig. S6, http://
links.lww.com/ALN/C743), sex (Supplemental Digital
Content fig. S7, http://links.lww.com/ALN/C743), and
age (Supplemental Digital Content fig. S8, http://links.
lww.com/ALN/C743) can be found in the supplemental
materials.
Simulations
Simulation of Target-controlled Infusion Using the
Hannivoort Model
To better illustrate the differences between the models and
the possible implications in the clinical setting, we simu-
lated target-controlled infusion administrations according
to the linear pharmacokinetic model by Hannivoort et
al.10 with increasing target concentrations. The aim of
the simulation was to identify the concentration range in
which predictions from our final nonlinear model would
deviate from the expected concentrations according to
a target-controlled infusion system based on the linear
pharmacokinetic model by Hannivoort et al.10 Figure 4
shows the simulated plasma concentrations for the target-
controlled infusion system based on the linear pharma-
cokinetic model by Hannivoort et al.10 and the predicted
plasma concentrations and the 95% prediction interval
for our final nonlinear model. The predicted concentra-
tions from the final nonlinear model and the target-con-
trolled infusion model are in good agreement until 2 ng
· ml–1. Beyond this target concentration, a discrepancy

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 Dexmedetomidine Elicits Nonlinear Kinetics

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Fig. 2. Goodness of fit diagnostic plots for the final model. The top panels show the population (left) and individual (right) predictions on the
y-axis plotted against the observed dexmedetomidine plasma concentrations. The continuous red line is a polynomial logistic regression used
as an aid to identify biased from the line of unity (when applicable). The middle panels show the individual conditional weighted residuals
plotted against the individual predictions (left) and time (right). The bottom panels show the conditional weighted residuals plotted against
the individual predictions (left) and time (right).

is seen between the predicted concentrations accord-
ing to the target-controlled infusion model and the pre-
dictions according to the nonlinear model with 62.1%
of the simulated individuals being above the target at a
target of 3 ng · ml–1 to 80.4% at 5 ng · ml–1. The inac-
curacy of the linear target-controlled infusion model,
expressed as the ratio between the predicted concentra-
tion according to our final nonlinear model and the tar-
get concentration, was 0.89 (95% prediction interval = 0.7
to 1.2) at 1 ng · ml–1, 0.97 (0.7 to 1.6) at 2 ng · ml–1, 1.1 (0.7
to 2.0) at 3 ng · ml–1, 1.2 (0.7 to 2.4) at 4 ng · ml–1, and 1.4
(0.8 to 2.9) at 5 ng · ml–1.
Another scenario that we explored was effect-site target-
controlled infusion. Figure 5 shows effect-site target-
controlled infusion for increasing effect-site targets and the
resulting predicted plasma concentrations for the linear
pharmacokinetic model by Hannivoort et al.10 (blue lines
and shaded area) and our final nonlinear model (gray lines
and shaded area).The median predicted CMAX was 1.28-fold
higher (95% prediction interval: 0.4 to 2.8) at 0.1 ng · ml–1,
1.28-fold higher (0.4 to 2.5) at 0.2 ng · ml–1, 1.27-fold higher
(0.4 to 2.2) at 0.5 ng · ml–1, 1.29-fold higher (0.4 to 2.2)
at 1.0 ng · ml–1, 1.26-fold higher (0.4 to 2.0) at 2.0 ng · ml–1,
and 1.22-fold higher (0.4 to 2.0) at 3.0 ng · ml–1.
Critical Care Guidelines Recommended Dosing
Simulation
To further illustrate the implications of the nonlinear
pharmacokinetics of dexmedetomidine we simulated the
current European Medicines Agency (Amsterdam, The
Netherlands)–approved dosing regimen for sedation in the
ICU,19 consisting of a weight-based constant rate infusion

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 PERIOPERATIVE MEDICINE

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Fig. 3. Visual predictive check comparing linear and nonlinear pharmacokinetics models. Six subjects were simulated using both the final
nonlinear model (gray) and the previous linear model (blue). The subjects were selected based on the highest individual median performance
error on the linear kinetics model. The shaded area surrounding the model prediction median is the 95% prediction interval (based on 500
simulations). The red dots are the observations.

(µg ∙ kg–1 ∙ h–1). The upper panel of figure 6 shows that the
predicted CMAX according to our final nonlinear model reaches
3.2 ng · ml–1 (95% prediction interval, 2.2 to 4.8) after the ini-
tial loading dose, whereas the predicted CMAX according to the
linear pharmacokinetic model by Hannivoort et al.10 is 1.5 ng
· ml–1 (95% prediction interval, 1.1 to 2.0). The lower panel
in figure 6 depicts the maximum recommended continuous
administration of dexmedetomidine and shows a good agree-
ment between the median predicted plasma concentrations for
both models. However, figure 6 suggests that with time, the
variability in the population increases, with the 95% prediction
interval increasing from 0.95 to 2.02 ng · ml–1 1 h after the dose
to 1.80 to 20.84 ng · ml–1 toward the end of the 24-h infusion
period.At the end of the 24-h infusion, 62.8% of the simulated
subjects had plasma concentrations above the median concen-
tration predicted with the linear model, 24.3% twice as high
and 7.3% five times higher than the concentrations predicted
by the linear model.
Discussion
In this pooled analysis, we have shown that dexmedeto-
midine administered to healthy subjects exhibits nonlinear
clearance, which may lead to higher than expected plasma
concentrations with increasing drug exposure. Dyck et al.6
were the first to suggest nonlinearity in dexmedetomi-
dine pharmacokinetics. In line with Dyck et al.,6 Dutta
et al.11 hypothesized that a dose-related reduction in car-
diac output resulted in a decrease in hepatic blood flow
and consequently a reduced dexmedetomidine clearance.
Interestingly, Dutta et al.11 concluded that based on their
data from 10 healthy volunteers, there was no statistically
significant difference in the fit of a cardiac output inde-
pendent and dependent pharmacokinetic model. In 2012,
Iirola et al.20 reported a positive association between cardiac
output and dexmedetomidine clearance in eight patients
admitted to the ICU with a continuous infusion of dexme-
detomidine. Unfortunately, Iirola et al.20 did not compare a
model with cardiac output against a nonlinear pharmacoki-
netic model without cardiac output, like the model we are
proposing. Such a comparison would have given an indica-
tion of whether cardiac output is a better surrogate than the
dexmedetomidine plasma concentration for describing the
nonlinear dexmedetomidine pharmacokinetic model. At
the same time, it is noteworthy that the subjects in the study
by Iirola et al.20 received concomitant medication known/
suspected to decrease cardiac output (e.g., propofol), which
might have confounded the association between dexmede-
tomidine plasma concentration and cardiac output.

286 Anesthesiology 2022; 136:279–92 Alvarez-Jimenez et al.

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 Dexmedetomidine Elicits Nonlinear Kinetics

15
80.4 %

Dexmedetomidine concentration (ng/mL)

10
73.5 %

62.1 %
5

45.9 %

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36 %
0

0 200 400 600 800 1000

time (min)

Fig. 4. Target-controlled infusion simulation comparing linear and nonlinear pharmacokinetics models. Plasma simulated concentrations
against time in an increasing dose scheme. Simulations were performed using the linear model as the driving model (blue); i.e., the needed
dose to accomplish as soon as possible the given target concentration (1 to 5 ng · ml–1) was calculated using the target-controlled infusion
algorithm. Using this same dose as a fixed variable, the theoretical real concentration was calculated to be used in the nonlinear parameters
(gray). The shaded area surrounding the median prediction is the 95% prediction interval. Percentages at each dose target depict the per-
centages of individuals with concentrations above the target plasma concentration. For the simulations, 1,000 randomly generated subjects
were used. Simulated demographics (age, weight, and sex) were also sampled from the model.

Our analysis based on continuous cardiac output mea- over 10 min, i.e., 6 µg · kg–1 · h–1), and the finding of
surements in 48 healthy volunteers has shown that cardiac decreased cardiac output in these dose groups is therefore
output is not a significant predictor for between-subject less representative of the current use of dexmedetomidine.
variability in dexmedetomidine clearance. We also showed Our model, most notably equation 3, implies that dex-
that changes from baseline cardiac output are not correlated medetomidine clearance decreases with increasing dexme-
with within-subject longitudinal changes in dexmedetomi- detomidine plasma concentrations. Saturation of metabolic
dine clearance. clearance at higher concentrations is not expected to have
Bloor et al.21 studied the hemodynamic changes, includ- an influence on dexmedetomidine clearance because dex-
ing cardiac output, induced after IV dexmedetomidine medetomidine is considered a high extraction ratio drug.
bolus doses of 0.25, 0.5, 1.0, and 2.0 µg · kg–1 administered According to the well stirred liver model, liver blood flow
over 2 min. These authors found that cardiac output (and and not enzyme activity is the main determinant of clear-
systolic blood pressure) in the lowest dose group was not ance for high extraction ratio drugs. This reasoning is sup-
different from placebo. In the trial by Hannivoort et al.10 ported by experimental work by Kohli et al.22 and Wang
and the trial by Weerink et al.,9 the dexmedetomidine infu- et al.,23 who observed no influence of CYP2A6 metabolizer
sion rate was limited to 6 µg · kg–1 · h–1 for target concen- status on dexmedetomidine pharmacokinetics.
trations less than 5 ng · ml–1 and to 10 µg · kg–1 · h–1 for We hypothesize that dexmedetomidine alters the liver
higher targets. These rate limitations imply that the bolus blood flow–to–cardiac output ratio in a concentration-
doses given by the target-controlled infusion system imme- dependent manner (in line with the other hemodynamic
diately after changing the target-controlled infusion target effects of dexmedetomidine21,24,25). Such a phenomenon
were limited to a rate of 0.20 µg · kg–1 and 0.33 µg · kg–1 per could account for the apparent lack of correlation between
2 min, respectively. In that respect, the absence of a signifi- cardiac output and dexmedetomidine clearance and the
cant dexmedetomidine-induced decrease in cardiac output concentration-dependent nature of the decrease in clear-
in our data (as shown in Supplemental Digital Content fig. ance. Interestingly, a similar phenomenon was observed
S1, http://links.lww.com/ALN/C743) is not surprising for propofol, another high extraction ratio drug. Peeters
and completely in line with the seminal work by Bloor et et al.26 demonstrated that in critically ill patients, there was
al.21 The 0.5, 1.0, and 2.0 µg ∙ kg–1 bolus doses studied by no relationship between propofol clearance and cardiac
Bloor et al.21 were infused at higher infusion rates than what output, whereas hepatic blood flow (measured by sorbitol)
is recommended nowadays on the drug label (1 µg · kg–1 was positively correlated with propofol clearance. Although

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 PERIOPERATIVE MEDICINE

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Fig. 5. Effect-site target-controlled infusion simulations comparing linear and nonlinear pharmacokinetics models. Plasma simulated con-
centrations against time in an increased dosing scheme. Simulations were performed using the concentrations in the effect-site compartment
as the driving model. Six target concentrations were explored: 0.1, 0.2, 0.5, 1, 2, and 3 ng · ml–1. The theoretical concentration was calculated
using both the nonlinear (gray) and linear (blue) kinetic models. The effect-site concentration in the right vertical axis is represented by the
purple discontinuous line. The shaded area surrounding the median prediction is the 95% prediction interval. For the simulations, 1,000
randomly generated subjects were used. Simulated demographics (age, weight, and sex) were also sampled from the model.

the analysis by Peeters et al.26 might have been confounded
by the presence of extrinsic factors, such as comedication,
their work supports our hypothesis that, in some cases, the
liver blood flow–to–cardiac output ratio is not constant,
leading to no (or poor) correlation between cardiac output
and drug clearance.
Our final nonlinear three-compartment pharmacoki-
netic model successfully predicted dexmedetomidine con-
centrations over a wide concentration range. We found that
weight, age, and sex are significant covariates for the phar-
macokinetics of dexmedetomidine. In addition to weight-
based allometric scaling, we identified the importance of
incorporating age into the model to enhance accuracy
of allometric scaling for the estimation of the clearance.
Clearance was also inversely proportional to the age in sev-
eral previous models.3 Despite the lack of a clear consensus
as to whether age correlates with the clearance or volumes
of distribution, three studies20,27,28 have reported positive
results of age as covariate over a wide age range.With refer-
ence to sex, this is the first data set that demonstrates varia-
tion between females and males. Differences have also been
reported in cardiac output and liver perfusion between
females and males in addition to the body fat composition,29
which may account for the pharmacokinetic differences
between the sexes. Supplemental Digital Content figure S9
(http://links.lww.com/ALN/C743) depicts the result of a
simulation in subjects with different covariates, providing
evidence that male subjects with increased age and a low
total body weight might be subjects at risk of nonlinear
pharmacokinetics.
Our final model assumes that clearance is completely
inhibited at very high dexmedetomidine concentrations.
This assumption was challenged by an attempt to estimate
an IMAX parameter in the model, describing the maximum
proportional decrease in dexmedetomidine clearance
at very high concentrations. However, we encountered
numerical difficulties when trying to estimate IMAX, and this
approach was abandoned. According to our final model,
the mean maximal decrease in dexmedetomidine clear-
ance across individuals was 55.2% (range, 23.3 to 82.7%).To
estimate an IMAX parameter from experimental data, higher
dexmedetomidine concentrations than the ones reported in
our study are likely necessary.
In our study, the plasma concentrations were from arte-
rial blood samples taken during (45% of total number of
samples) or after (55%) drug infusion. Incomplete mixing

288 Anesthesiology 2022; 136:279–92 Alvarez-Jimenez et al.

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 Dexmedetomidine Elicits Nonlinear Kinetics

dexmedetomodine loading dose of 1 ug/kg in 10 min followed by a continuous

4
Dexmedetomidine concentration (ng/mL)

one−hour 0.7 ug/kg/hr infusion according to the Summary of Medical Product

Characteristics (SmPC) for sedation in ICU patients
non−linear elimination model
3

linear elimination model

2
1

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0

0 50 100 150 200

time (min)
Dexmedetomidine concentration (ng/mL in log scale)

20.0
5.0
2.0
1.0
0.5

dexmedetomidine continuous dose (1.4 ug/kg/hr) in 24 hrs

non−linear elimination model
0.2

linear elimination model

0.1

0 500 1000 1500 2000

time (min)

Fig. 6. Weight dosed simulation using the current recommended dosing strategies for dexmedetomidine in clinical practice. The upper
panel illustrates the weight-only (and not target-controlled infusion) currently recommended dosing strategy for patients in the intensive care
unit (ICU) receiving sedation using dexmedetomidine. A dexmedetomidine loading dose of 1 μg · kg–1 administered in 10 min followed by a
continuous 0.7 μg · kg–1 · h–1 infusion for 1 h was simulated in 1,000 randomly generated 40-yr-old subjects with a total body weight of 80 kg.
The lower panel simulates the maximum recommended administration dose of 1.4 μg · kg–1 · h–1 without a loading dose for 24 h in 1,000
subjects with the same demographics as above.

of first-pass and recirculated drug concentrations, most nonlinear model on the remaining 419 (55% of total number
notably in the presence of reduced cardiac output, affects of observations) measured dexmedetomidine concentra-
measured plasma concentrations from samples taken during tions. The results showed strong statistical evidence in favor
drug infusion.30 As a consequence, the apparent nonlin- of the nonlinear model (Δ objective function value = –63;
earity that we described could have originated from the P value likelihood-ratio test < 0.001), thereby demonstrat-
amplifying effect of incomplete mixing rather than from a ing that potential incomplete mixing of arterial samples
concentration-dependent decrease in clearance. To test this during drug infusion is not confounding our conclusions.
hypothesis, we excluded all observations that were collected To identify the prediction discrepancies between our
during or shortly after (less than 5 min) drug infusion and final nonlinear pharmacokinetic model and the linear phar-
reestimated the linear three-compartmental model and the macokinetic model by Hannivoort et al.10 that is currently

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 PERIOPERATIVE MEDICINE
available in target-controlled infusion systems, we simu-
lated different scenarios. For plasma target-controlled infu-
sion, we found that the model predictions for both models
for plasma targets less than 2 ng · ml–1 were very consis-
tent. Conversely, when aiming for higher targets, caution
is advised, and small increments in targets should be used
due to nonlinear clearance. Effect-site target-controlled
infusion simulations highlighted the discrepancies between
both models when utilizing specific effect compartment
concentrations. Effect-site target-controlled infusion differs
from the previous plasma concentration target-controlled
infusion because the aimed concentration is to be found
at the (theoretical) compartment concentration where
the desired effect is expected, in this case sedative effect
in the central nervous system. The effect-site target-con-
trolled infusion has the advantage of a quicker appearance
of the desired effect because the system administers an ini-
tial bolus to achieve the target concentration at the effect
site. Unfortunately, this initial bolus can lead to adverse
effects as the plasma concentrations can abruptly peak.
Even though there was a difference between the linear
and nonlinear model plasma concentrations, the CMAX did
not increase in the target range from 0.1 to 3.0 ng · ml–1
with a maximum ratio between 1.22 and 1.28. As a final
example of the implications of the model, we simulated the
current guideline-recommended doses for sedation for ven-
tilated patients in the ICU.19 Figure 6 clearly demonstrates
that the predicted concentration would have doubled in the
nonlinear model resembling the real plasma concentrations
compared to the previous linear model during the initial
1 µg · kg–1 loading dose administration. In addition, fig-
ure 6 also identifies that long-term infusion (24 h) can cause
higher plasma concentrations in a minority of subjects with
a low individual C50 value. Subjects in the extremes of age
were not included in the trial. Future studies should exam-
ine very elderly as well as pediatric subjects and multiple
comorbid patients. An enhanced understanding of the eti-
ologic mechanisms of nonlinearity are needed to further
understand the pharmacology of dexmedetomidine, and if
proven favorable for patient outcome, commercially avail-
able target-controlled infusion pumps should include a
more advanced algorithm to include the solution of non-
linear kinetics. Today, target-controlled infusion steering
algorithms implemented in clinically available pumps sup-
port only linear kinetics.31
In this study, we developed a nonlinear three-compart-
ment pharmacokinetic model that predicted dexmede-
tomidine at various concentration ranges. As opposed to
previous studies, our model may permit a more accurate
dosing at high plasma concentrations (greater than 2 ng
· ml–1). We identified weight, age, and sex as significant
covariates in our pharmacokinetic model. Administration
of up to 2 ng · ml–1 may be safe to utilize in the previously
developed dexmedetomidine pharmacokinetic model with
linear or first-order pharmacokinetics. Caution is advised in
290 Anesthesiology 2022; 136:279–92
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the ICU for patients at risk during long-term administra-
tion and during an initial loading dose when following the
dosing strategies of the current dosing guidelines.
Acknowledgments
The authors thank Rob Spanjersberg, R.N. (University
Medical Center Groningen, Groningen, The Netherlands),
for coordinating and facilitating this research project, as well
as all research personnel that collected the data of the two
clinical studies. The authors also thank all of the volunteers
who contributed to the two previous clinical trials and
David A. Newhall, M.D. (North Bristol National Health
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Service Trust, Bristol, United Kingdom), for his help with
thoroughly reviewing the article.
Research Support
Supported by the Department of Anesthesiology, University
of Groningen and University Medical Center Groningen,
Groningen, The Netherlands.
Competing Interests
Dr. Struys’s research group/department received (over the
last 3 yr) research grants and consultancy fees from the
Medicines Company (Parsippany, New Jersey), Masimo
(Irvine, California), Fresenius (Bad Homburg, Germany),
Dräger (Lübeck, Germany), Paion (Aachen, Germany),
and Medtronic (Dublin, Ireland). Dr. Struys also receives
royalties on intellectual property from Demed Medical
(Temse, Belgium) and Ghent University (Ghent,
Belgium). He is an editorial board member and director
for the British Journal of Anesthesia and associate editor
for Anesthesiology. He was not involved in the editorial
process of this publication. The other authors declare no
competing interests.
Correspondence
Address correspondence to Dr. Colin: University
Medical Center Groningen, University of Groningen,
P.O. Box 30001, 9700 RB Groningen, The Netherlands.
p.j.colin@umcg.nl. This article may be accessed for per-
sonal use at no charge through the Journal Web site,
www.anesthesiology.org.
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ANESTHESIOLOGY REFLECTIONS FROM THE WOOD LIBRARY-MUSEUM

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Conjuring Childhood Dreams, Pond’s Extract “Cures All”

Patients in the late nineteenth century often feared the expense and inconsistency of physician remedies, reach-
ing for drugstore “cure-alls” instead. Store clerks in the United States handed out trade cards that advertised
these “patent medicines,” some of which contained high levels of alcohol, morphine, or cocaine. Capturing the
hope and innocence of youth, these cheerful collectibles became a scrapbooking favorite. In the example above,
a popular trade card celebrates “Pond’s Extract: Vegetable Pain Destroyer,” brainchild of pharmacist Theron T.
Pond. A dream of childhood imbues the image; an angel-winged girl holds a bright umbrella over a monocled
boy on an iridescent seashore. “What’s on the back?” the card beckons (bottom). Its reverse unveils the acronym
“POND’S EXTRACT” with its corresponding indications: “Piles, Old sores, Neuralgia, Diphtheria, Sprains,
Eyes inflamed, Xternal Use, Tonsilitis, Rheumatism, Accidents, Catarrh, Throat sore.” A topical remedy of witch
hazel (Hamamelis virginiana) and dilute alcohol, Pond’s Extract was beloved for its skin-protectant and anti-in-
flammatory properties. In the early twentieth century, the T.T. Pond Company would also develop Pond’s Cold
Cream, now considered a classic beauty product. (Copyright © the American Society of Anesthesiologists’
Wood Library-Museum of Anesthesiology, Schaumburg, Illinois. www.woodlibrarymuseum.org)
Jane S. Moon, M.D., Assistant Clinical Professor, Department of Anesthesiology and Perioperative Medicine, University
of California, Los Angeles, California.

292 Anesthesiology 2022; 136:278–92 Alvarez-Jimenez et al.

Copyright © 2021, the American Society of Anesthesiologists. All Rights Reserved. Unauthorized reproduction of this article is prohibited.