KJA

Clinical Research Article

pISSN 2005-6419 • eISSN 2005-7563

Estimation of the effect-site

Korean Journal of Anesthesiology equilibration rate constant using
the time-to-peak effect of muscle
relaxants measured by train-of-
four stimulation during general
anesthesia induction
Se Yeon Park, Hyun Jung Kim, Yun Suk Choi, So-hui Yun, and
Jong Cook Park
Department of Anesthesiology and Pain Medicine, Jeju National University Hospital, Jeju, Korea

Background: The concept of the effect-site concentration of anesthetic agents is important. The effect compartment
model can be explained using the concepts of effect-site concentration and effect-site equilibration rate constant (ke0).
This study confirms that the time-to-peak effect (tpe) can be measured easily in clinical practice by applying a priming
dose and train-of-four (TOF) during general anesthesia induction, and ke0 can be calculated from the tpe of the four mus-
cle relaxants that are commonly used in general anesthesia.
Methods: Eighty patients who received general anesthesia were divided into the succinylcholine, rocuronium, atracuri-
um, or vecuronium groups. Priming doses of muscle relaxants were administered. The effects of muscle relaxants were
quantified by recording the twitch response of the adductor pollicis muscle after stimulating the ulnar nerve. The tpe was
measured at the lowest TOF value. ke0 was calculated from the measured tpe.
Results: The ke0 values of the succinylcholine, rocuronium, atracurium, and vecuronium groups were 0.076 (0.030)/min,
0.228 (0.122)/min, 0.062 (0.011)/min, and 0.077 (0.019)/min, respectively.
Conclusions: It is possible to estimate ke0 from the tpe of muscle relaxants using a priming dose and TOF during general
anesthesia induction.

Keywords: Atracurium; General anesthesia; Rocuronium; Succinylcholine; Train-of-four; Vecuronium.

Corresponding author: Jong Cook Park, M.D., Ph.D.

Department of Anesthesiology and Pain Medicine, Jeju National University Hospital, 15, Aran 13-gil, Jeju 63241, Korea
Tel: 82-64-717-2029, Fax: 82-64-717-2042
Email: pjcook@[Link]
ORCID: [Link]
This is a thesis for a Master’s degree by Se Yeon Park.
It was presented at the Annual Meeting of the Korean Society for Anesthetic Pharmacology, April 2016, Sejong University, Seoul, Korea.
Received: December 29, 2016. Revised: February 17, 2017 (1st); April 5, 2017 (2nd); May 17, 2017 (3rd). Accepted: May 31, 2017.
Korean J Anesthesiol 2018 April 71(2): 113-119
[Link]

CC This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ([Link]

licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright ⓒ The Korean Society of Anesthesiologists, 2018 Online access in [Link]
Etimation of the ke0 using the tpe VOL. 71, NO. 2, APRIL 2018

Introduction (File No. 2015-12-004-001), a written informed consent was

obtained from each patient. Eighty patients who were undergo-
The concepts of time and concentration are important for ing elective surgery under general anesthesia for non-systemic
the administration of drugs used in anesthesia. Safe anesthesia is diseases such as otitis media and chronic rhinitis were selected
achieved by accurately understanding the effect time of the drug by referring to another study [5]. All patients belonged to the
and the dose-response relationship. American Society of Anesthesiologists (ASA) class 1 or 2. Pa-
The time at which the effect of the drug begins is known as tients with an ASA class 3 or higher, neuromuscular diseases,
the onset time of the drug. The time at which the effect is maxi- liver or kidney diseases, and those without a body mass index of
mized is the time-to-peak effect (tpe). However, since blood is 18.5–30.0 kg/m2 were excluded. Eighty patients who agreed to
not an effect site of the drug but transports the drug to an effect the study protocol were randomly divided into the succinylcho-
site, the concept of an effect-site concentration that can repre- line, rocuronium, atracurium, and vecuronium groups. Twenty
sent the effect is needed. When the drug is administered, the patients were assigned to each group.
plasma concentration gradually decreases from the maximum Standard monitoring devices such as non-invasive blood
value, and the effect-site concentration gradually increases. The pressure (NIBP), electrocardiogram, and pulse oximetry were
tpe is the time at which the plasma concentration and the effect- used in all patients, who remained in the supine position in the
site concentration are equal, and the effect-site concentration is operating room. A kinemyography (KMG) (NMT Mechanosen-
maximum [1]. sor, Datex-Ohmeda, Finland) sensor was placed on the thumb
The effect compartment model was designed to explain the and index finger of the arm without the NIBP monitoring de-
effect-site concentration. The effect-site equilibration rate con- vice, and electrodes were attached to the wrist where the ulnar
stant (ke0), which is derived from this model, is the first-order nerve passes. After preoxygenation, anesthesia was induced with
rate constant between the effect site and plasma. thiopental sodium 5 mg/kg, 100% oxygen, and 3–5% sevoflu-
The traditional approaches to calculating the ke0 are the rane. The baseline value was measured by stimulating the ulnar
parametric or sequential pharmacokinetic-pharmacodynamic nerve with a maximal stimulation of up to 70 mA, and TOF
method and the non-parametric pharmacodynamic modeling. values were monitored every 10 seconds. The muscle relaxants
The disadvantage of these methods is the need for a wide range were diluted with normal saline and were prepared as 10 mg/ml
of drug effects, which start at baseline, achieve a maximum ef- of succinylcholine chloride, 10 mg/ml of rocuronium bromide,
fect, and then return to baseline. The calculation of the ke0 of 10 mg/ml of atracurium besylate, and 1 mg/ml of vecuronium
the drug requires the measurement of the plasma concentration bromide. After one-fifth of the muscle relaxant dose used in the
and pharmacokinetic parameters after drug administration induction of general anesthesia was intravenously administered
combined with the evaluation of the effect of the drug. This ap- with a priming dose, the time at which the TOF value was the
proach usually results in an ethically questionable situation or is lowest (Fig. 1A) and the effect-site concentration was the high-
unfeasible in the clinical setting [2]. est (Fig. 1B) was measured and recorded. We used 0.2 mg/kg of
The estimation of ke0 using tpe is an alternative method [2]. succinylcholine, 0.1 mg/kg of rocuronium, 0.1 mg/kg of atracuri-
ke0 can be estimated by measuring tpe after the administration of um, and 0.01 mg/kg of vecuronium as the priming dose. The es-
a single-dose or by evaluation of the effect-site concentration- timated effect-site equilibration rate constant (estimated ke0) was
response curve during continuous infusion [3,4]. We estimated obtained by using the measured time-to-peak effect (measured
ke0 from the tpe of muscle relaxants using a single priming dose tpe). The method of Cortínez et al. [2] was used and is described
and train-of-four (TOF) during general anesthesia induction. A in the Appendix.
priming dose was used because identification of the lowest effect When the TOF value increased to more than 20% of the
of the drug was not possible with an induction dose. lowest value, the remaining dose (four-fifths of the total muscle
Knowledge of the tpe and ke0 of anesthetic agents is important relaxant dose) was intravenously administered. Endotracheal
for safe anesthesia. The purpose of this study is to confirm that intubation was performed when the TOF value was 0%. Data
tpe can be measured easily in clinical practice by applying a prim- were collected in real-time using a data collection program (S/5Ⓡ
ing dose and TOF during general anesthesia induction, and ke0 collect, Datex-Ohmeda, Finland).
can be calculated from the tpe of the four muscle relaxants that The estimated ke0 was obtained from the measured tpe, and all
are commonly used in general anesthesia. values were expressed as the mean (SD). Statistical analysis was
carried out using Statistical Package for Social SciencesⓇ Statis-
Materials and Methods tics version 24 (IBMⓇ, USA). P values smaller than 0.05 were
considered statistically significant.
After receiving approval from the Institutional Review Board A second objective of the study was the comparison of the

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KOREAN J ANESTHESIOL Park et al.

estimated ke0 value (obtained from the measured tpe) with the t-test.
effect-site equilibration rate constant proposed in other studies
(presented ke0) [6–9]. The estimated tpe can be calculated from Results
the presented ke0 using some equations (detailed in the Appen-
dix). The measured and estimated tpe and the presented and esti- The patient characteristics of the four muscle relaxant groups
mated ke0 within each group were compared using a one-sample are shown in Table 1. There were no significant differences in
these variables between the groups.
The measured tpe of each group was 2.2 (0.4) min in the
A
150 6 succinylcholine group, 5.1 (1.7) min in the rocuronium group,
9.6 (1.5) min in the atracurium group, and 9.6 (2.1) min in the
125 5 vecuronium group. The estimated ke0 was 0.076 (0.030)/min in
Measured tpe = 7.1 min the succinylcholine group, 0.228 (0.122)/min in the rocuronium
100 4
group, 0.062 (0.011)/min in the atracurium group, and 0.077

TOF count
TOF %

75 3 (0.019)/min in the vecuronium group.

Table 2 presents the results of the comparison of the esti-
TOF %
50
TOF count
2 mated ke0 and measured tpe with the effect-site equilibration rate
Priming dose constant proposed in other studies (presented ke0) [6–9] and the
25 Remaining dose 1
time-to-peak effect, which is calculated from the presented ke0
Intubation
(estimated tpe). The tpe of the succinylcholine group and the ke0 of
0 0
0 10 20 30 the vecuronium group were not significantly different, but these
Time (min) variables were significantly different in the other groups.
B
5 Cp (t) Discussion
Ce (t)
4 Knowledge about the tpe and ke0 of anesthetic agents is im-
Concentration (g/ml)

portant for safe anesthesia. Identification of the time of onset of

3 a drug is easy clinically, but the determination of tpe is not easy.
Estimated ke0 = 0.117 /min This study was designed to easily obtain the tpe and ke0 of anes-
2 thetic agents in clinical practice. In general anesthesia induction
involving a priming dose, TOF was used to measure tpe. We
1 developed a program using ExcelⓇ 2007 (Microsoft, USA) soft-
ware with equations (shown in the Appendix) that can calculate
0 ke0 from tpe. ke0 is estimated when tpe is input to the program. The
0 10 20 30 study design and the program can be simulated to obtain the
Time (min) ke0 of other drugs, and herein we estimated the ke0 of the four
Fig. 1. (A) Graphic representation of the induction-course of a muscle relaxants that are commonly used in anesthesia. The
rocuronium-induced non-depolarizing neuromuscular blockade in one measured tpe of the muscle relaxants was obtained by TOF mon-
patient. Measured tpe is the time-to-peak effect obtained by using train- itoring during general anesthesia induction and administering a
of-four (TOF). (B) Concentration and time course of plasma Cp(t)
and effect-site Ce(t). Estimated ke0 is the value calculated using the priming dose of each muscle relaxant. According to the princi-
measured time-to-peak effect. ple of linear pharmacokinetics, because plasma concentration or

Table 1. Patient Characteristics

Succinylcholine group Rocuronium group Atracurium group Vecuronium group
(n = 20) (n = 20) (n = 20) (n = 20)

Age (yr) 48 (17) 47 (16) 48 (17) 51 (11)

Sex (M/F) 13/7 13/7 14/6 7/13
Body weight (kg) 64.7 (13.1) 65.5 (14.7) 65.8 (8.3) 64.2 (12.5)
Height (cm) 163.7 (10.6) 162.5 (11.6) 164.9 (7.3) 160.0 (8.3)
Values are expressed as mean (SD).

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Etimation of the ke0 using the tpe VOL. 71, NO. 2, APRIL 2018

Table 2. Comparison of the Time-to-peak Effect (tpe) and the Effect-site Equilibration Rate Constant (ke0) for Each Muscle Relaxant
Succinylcholine group Rocuronium group Atracurium group Vecuronium group
(n = 20) (n = 20) (n = 20) (n = 20)

Measured tpe (min) 2.2 (0.4) 5.1 (1.7) 9.6 (1.5) 9.6 (2.1)
↓
Estimated ke0 (/min) 0.076 (0.030) 0.228 (0.122) 0.062 (0.011) 0.077 (0.019)

Estimated tpe (min) 2.3 6.3 8.7 8.4

↑
Presented ke0 (/min) 0.058 0.127 0.068 0.085

P value* 0.127 0.005 0.013 0.020

P value† 0.013 0.002 0.027 0.066
Values are expressed as mean (SD). Measured tpe is the tpe obtained by using train-of-four (TOF). Estimated ke0 is the value calculated using the
measured tpe. Estimated tpe is the value calculated using the presented ke0. Presented ke0 is the ke0 proposed in other studies. References of the presented
ke0 (/min): succinylcholine [6], rocuronium [7], atracurium [8], vecuronium [9]. →: the direction of calculation, tpe (min): time-to-peak effect, ke0
(/min): effect-site equilibration rate constant. *Comparison of the measured tpe and the estimated tpe. †Comparison of the presented ke0 and the
estimated ke0.

elimination is proportional to the dose, ke0 is not affected [10]. obtained, and additional dosages and time points can be deter-
Therefore, ke0 can be obtained by the intravenous administration mined. Therefore, ke0 of muscle relaxants is important in general
of the priming dose. anesthesia. In other words, the tpe and ke0 of muscle relaxants
The TOF stimulation method is used to determine the quan- are used clinically to determine the timing of intubation of each
titative relationship between the effect-site concentration and muscle relaxant and help to determine when additional doses
the drug effect. After bolus administration of the muscle relax- should be administered during anesthetic maintenance. ke0 can
ant, the time at which the TOF value is the lowest is the tpe. The also be used for target-controlled infusion [1].
advantages of TOF stimulation are its noninvasiveness, ease of Because the estimated ke0 was obtained from the measured tpe
use, and cost-effectiveness. TOF stimulation has been applied of the four muscle relaxants commonly used in general anesthe-
with a minimum interval of 10 seconds and is known to be more sia, it has significance as the estimated ke0 of each muscle relax-
sensitive than single twitch [11–13]. In addition, TOF stimula- ant in the same study design. Our results indicated a variation in
tion is more advantageous than single twitch because the latter the measured tpe for each patient even with the same muscle re-
needs to establish a baseline value before the administration of laxant. Since the estimated ke0 was obtained from each measured
muscle relaxants. Mechanomyography (MMG) has long been tpe, the former was also affected by an individual bias. However,
regarded as the gold standard of neuromuscular monitoring, but even in cases in which the same drug was administered at the
the mechanomyogram is relatively bulky and difficult to apply, same dose, the effects were different for each patient because
which limits its clinical use [14,15]. The KMG used in this study of the pharmacokinetic and pharmacodynamic variability [1].
can be easily applied in clinical practice without significant dif- Pharmacokinetic variability is defined as the condition in which
ferences from the results of MMG, electromyography (EMG), a time-concentration curve varies from person to person. Phar-
acceleromyography, and phonomyography [15–17]. However, macodynamic variability is defined as a condition in which a re-
some studies suggest that KMG rather than EMG is overesti- sponse varies from person to person at the same concentration.
mated [18], which may be a limitation of this study. This limitation can be overcome by population analysis. However,
The determination of the estimated ke0 from the measured tpe although studies have suggested the various pharmacokinetic
only requires a portion of the response curve, without the need parameters, we selected the same pharmacokinetic parameters
to evaluate the complete course of the drug effect, and is possible for each group of muscle relaxant [6,20–22]. Therefore, it was
by measuring the drug effect during general anesthesia induc- thought that there was no variation in the estimation of the ke0
tion [19]. ExcelⓇ 2007 (Microsoft, USA) software was used to by using pharmacokinetic parameters.
calculate the estimated ke0 rather than an expensive commercial The second objective of our study was to compare the tpe and
program. ExcelⓇ is relatively easy to use to obtain the estimated ke0 of other studies with the tpe and ke0 of our study to support
ke0 from the measured tpe, and the estimated ke0 can be simulated the accuracy of our results. The tpe of the succinylcholine group
for drugs other than muscle relaxants. and the ke0 of the vecuronium group were not significantly
Since the drug volume of distribution in the effect site can be different, but these variables were significantly different in the
determined from the ke0, the initial loading dose and tpe can be other groups (Table 2). In the rocuronium group, the presented

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KOREAN J ANESTHESIOL Park et al.

ke0 that we quoted in another study was 0.127/min, but ke0 values drugs, and we estimated the ke0 of the four muscle relaxants
suggested in that study were 0.127/min and 0.09/min [7]. For that are commonly used in anesthesia. The estimated ke0 can be
atracurium, a study suggests a ke0 of 0.043/min [23], the other obtained from the measured tpe of these four muscle relaxants
study proposes 0.068/min. The difference between this study using a priming dose and TOF stimulation during general an-
and other studies is the use of isoflurane or propofol as the anes- esthesia induction, and individual deviations in tpe and ke0 are
thetic agent as well as the use of TOF or single twitch. As inha- observed.
lation anesthetics enhance the effect of muscle relaxation, they
likely affect the muscle relaxation effect. TOF stimulation and Acknowledgments
single twitch were considered study variants with a high sensi-
tivity but a low specificity. This research was supported by the 2017 scientific promotion
The estimated ke0 was compared with the presented ke0, and program funded by Jeju National University.
the estimated tpe (calculated from the presented ke0) was verified
by using the measured tpe. In this study, the estimated ke0 of suc- ORCID
cinylcholine, rocuronium, and atracurium was different from
the presented ke0. Further studies are necessary to elucidate these Hyun Jung Kim, [Link]
results. Yun Suk Choi, [Link]
In conclusion, this study was designed to easily obtain the tpe So-hui Yun, [Link]
and ke0 of anesthetic agents in clinical practice. The study design Jong Cook Park, [Link]
and the program can be simulated to obtain the ke0 of other

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Appendix

The plasma concentration (Cp) is a composite convolution of the dosage regimen (D) and the unit disposition function (UDF). Cp

can be summarized by the following equation:

C p (t )  D(t )  UDF(t ) Equation 1

where  represents a convolution. When t is 0 and D is 1, Cp(t) becomes UDF(t). The UDF(t) of the multi-compartment model is

presented by the following equation [10]:

n
UDF (t )   Ai  e i t Equation 2
i 1

where Ai is the coefficient and l i is the exponent, and these variables are obtained from the volume (Vi) and the micro-rate constant

(kij) shown in Table A.

In the compartment models, the effect-site compartment includes the effect-site equilibration rate constant (ke0), and the volume of

the effect site and the drug movement with the central compartment are negligible. The effect-site concentration (Ce) is represented by

the following equation [10]:

n
ke 0  Ai
Ce (t )  D(t )    (ei t  eke 0 t ) Equation 3
i 1 ke 0  i

Since the rate of increase or decrease of the effect-site concentration is 0 at the time-to-peak effect (tpe), when C'e(t) is 0, t is tpe. The

tpe is estimated by substituting ke0 into the following equation [10]:

n
ke 0  Ai
Ce (t )  D(t )    (i  ei t  ke 0  eke 0 t )  0 Equation 4
i 1 ke 0  i

In contrast, ke0 can be estimated from the measured tpe. Considering that the plasma concentration and the effect-site concentration

are in equilibrium at the measured tpe, ke0 can be calculated by the following equation [10]:

{C p (t p e )  Ce (t p e )}2  0 Equation 5

These equations were used in ExcelⓇ 2007 (Microsoft, USA) to construct a simulation program. The program can calculate tpe using

ke0, and can derive ke0 by substituting tpe. The pharmacokinetic parameters used for each muscle relaxant are shown in Table A.

Table A. Pharmacokinetic Parameters of Muscle Relaxants

Succinylcholine: Rocuronium: Atracurium: Vecuronium:
Roy et al. [6] Wierda et al. [20] Kitts et al. [21] Sohn et al. [22]

k10 (/min) 5.0 (2.6) 0.1 0.166 0.099 (0.049)

k12 (/min) 2.9 (3.9) 0.21 0.217 0.23 (0.18)
k21 (/min) 1.6 (0.4) 0.13 0.123 0.19 (0.12)
k13 (/min) - 0.028 - 0.086 (0.024)
k31 (/min) - 0.01 - 0.013 (0.007)
V1 (L/kg) 0.009 (0.003) 0.045 0.032 0.048 (0.02)
V2 (L/kg) 0.016 0.073 0.068 0.054 (0.031)
V3 (L/kg) - 0.126 - 0.38 (0.22)
All data presented as mean (SD). kij (/min): micro-rate constant. Vi (L/kg): volume of distribution of the three compartments.

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