Potential pitfalls of propofol target controlled infusion delivery related

Pharmacological Reports
Copyright © 2012
2012, 64, 782–795
by Institute of Pharmacology
ISSN 1734-1140
Polish Academy of Sciences
Review
Potential pitfalls of propofol target controlled
infusion delivery related to its pharmacokinetics
and pharmacodynamics
Agnieszka Bienert1, Pawe³ Wiczling2, Edmund Grzeœkowiak1,
Jacek B. Cywiñski3, Krzysztof Kusza4
1
Department of Clinical Pharmacy and Biopharmacy, Karol Marcinkowski University of Medical Sciences,
Marii Magdaleny 14, PL 61-861 Poznañ, Poland
2
Department of Biopharmaceutics and Pharmacodynamics, Medical Univeristy of Gdañsk, Hallera 107,
PL 80-401, Gdañsk, Poland
3
Departments of General Anesthesiology and Outcome Research, Cleveland Clinic, 9500 Euclid Avenue,
Cleveland, Ohio 44195, USA
4
Department of Anesthesiology and Intensive Therapy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus
University in Toruñ, Marii Sk³odowskiej-Curie 9, PL 85-094 Bydgoszcz, Poland
Correspondence: Agnieszka Bienert, e-mail: [email protected]
Abstract:
Target controlled infusion (TCI) devices are increasingly used in clinical practice. These devices unquestionably aid optimization of
drug dosage. However, it still remains to be determined if they sufficiently address differences in pharmacological make up of individual patients. The algorithms guiding TCI pumps are based on pharmacological data obtained from a relatively small number of
healthy volunteers, which are then extrapolated, on the basis of sophisticated pharmacokinetic and pharmacodynamic modeling, to
predict plasma concentrations of the drug and its effect on general population. One has to realize the limitation of this approach: these
models may be less accurate when applied to patients in extreme clinical conditions: in intensive care units, with a considerable loss
of blood, severe hypothermia or temporary changes in the composition of plasma, e.g., hypoalbuminemia. In the future, data obtained under these “extreme” clinical circumstances, may be used to modify the dosage algorithms of propofol TCI systems to match
the clinical scenario.
Key words:
propofol, TCI systems, pharmacokinetics, pharmacodynamics
Introduction
Anesthetic management may influence the patient’s
post-procedural quality of life and state of health for
long years following the anesthesia. In particular, re-
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cent investigations focus on the effect of the depth of
anesthesia and postoperative cognitive function, as
well as long term mortality and morbidity [19, 40].
This aspect may be particularly important during total
intravenous anesthesia (TIVA) when target controlled
infusion (TCI) models are used for direct dosing of
Potential pitfalls of propofol target controlled infusion delivery
Agnieszka Bienert et al.
the anesthetic agent without assessing the end effects
of the delivered drugs on the central nervous system.
TCI models were developed on the basis of data from
healthy volunteers and may not be uniformly applicable to all clinical situations, ultimately resulting in under- or overdosing of the anesthetic; both situations
with non-trivial consequence.
Although not very frequent, awareness under general
anesthesia has quite dramatic impact on the postoperative quality of life and psychosocial outcomes, which
has been described in numerous prospective and retrospective studies [13, 26, 47]. According to the Declaration of Helsinki, published by the European Society of
Anesthesiology (ESA) in 2010, the speciality of Anesthesiology and Intensive Care guards the patient’s safety
and their quality of life after the surgery and anesthesia
[27]. In view of that fact, the Declaration by itself emphasises the role of education and the need to improve
anesthesiologists’ knowledge and qualifications in order
to reduce perioperative morbidity and mortality [27].
For thorough understanding of the pharmacokinetics
and pharmacodynamics of anesthetics, especially these
related to the limitations of propofol, TCI model is absolutely crucial to provide safe patient care. Also, understanding depth-of-anesthesia monitoring techniques, and
their applicability for different anesthethics cannot be
underestimated. At present, there is no medical evidence
that the routine use of devices to monitor the depth of
anesthesia (BIS, entropy, SFX, AEP – auditory evoked
potential) is a reliable protection from intraoperative
awareness [6, 27]. Furthermore, due to the human circadian rhythm, sex, concomitant diseases, including
these found in patients with extreme obesity and geriatric age, the pharmacodynamics of anesthetics, including
propofol, may vary. This understanding should be our
contribution to reduction of long term morbidity and perioperative mortality, with particular emphasis placed on
patients’ quality of life after anesthesia. Elements of
clinical pharmacology, which are part of the training
curricula, are frequently omitted in everyday education.
In consequence, in clinical practice anesthesiologists undergoing training do not fully understand the differences
between the patient’s clinical state related to infusion of
an anesthetic and the state of expected depression of the
central nervous system in the anesthetized patient [31].
The lack of understanding of the aforementioned
issues by anesthesia providers can cause potential
complications related to the maintenance of too light
or too deep plane of anesthesia which potentially can
have long-term consequences [25].
The significance of pharmacokinetic
and pharmacodynamic parameters in
intravenous anesthesia
Pharmacokinetic and pharmacodynamic modelling
(PK/PD) of drugs consists of a mathematical description of the relation between the dose and the concentration of a therapeutic substance (and its metabolites)
in the organism as well as the relation between the
concentration of the therapeutic substance and its effect on an end organ. It also describes the interaction
of drug concentration and response of the organism to
the drug as a function of time. In other words, pharmacokinetics describes what happens to the drug in
the organism, i.e., the processes of distribution, metabolism and excretion as well as absorption for extravascular administration. When the drug is administered intravenously, the process of absorption is omitted because the drug directly enters the blood,
whereas in extra vascular administrations such as subcutaneous, oral or intramuscular, the substance first
must be absorbed into the blood from the place of administration. Pharmacodynamics describes how the
drug affects the organism and how those effects
change in time. The knowledge of these processes and
practical application of the pharmacokinetics and
pharmacodynamics principles are necessary to assure
that the patient receives an optimal dose of drugs at
the right time. The anesthesiologist’s task is to ensure
an appropriate depth of anesthesia and to achieve stable dynamics of the circulatory system in response to
the surgical and perioperative stress. A particularly
desirable characteristic of an anesthetic is its titratibility, i.e., the immediate effect after administration and
absence of accumulation, the risk of which increases
especially in prolonged surgical procedures. Precise,
quantitative understanding of all the processes the
drug undergoes within a body and what clinical effect
they cause is possible only on the basis of PK/PD
models. They allow accurate description of both rapid
changes, which take place within seconds or minutes
after administration of the drug, and slow processes,
which take hours or days to complete. Also, they give
a possibility to understand and quantify the observed
clinical effects (e.g., the onset, duration, offset and
depth of anesthesia).
Drugs are not evenly and simultaneously distributed in the whole organism. The tissues where the
drug is distributed at the same rate and concentration
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783
are called compartments. The three-compartment
model of distribution is commonly used in anesthesia
to describe the pharmacokinetics of anesthetic agents.
The central compartment is the one to which the drug
is administered, i.e., the blood and tissues which are
very rich in blood vessels. Its volume, marked as V is
important when specifying induction doses of drugs.
As the volume of the central compartment decreases,
the required dose of the drug necessary to obtain
a specific effect is reduced. The drug will have
a higher concentration due to the fact that initially it is
distributed in a smaller volume. This phenomenon
can be observed for propofol in geriatric patients. The
reduced volume of the central compartment requires
a smaller induction dose of the drug. For anesthetic
drugs, two peripheral compartments are usually identified (V and V ). These are peripheral tissues into
which the drug penetrates quickly (V ) and slowly
(V ). A frequently used pharmacokinetic parameter
is the volume of distribution at steady state (V ),
which is the sum of all volumes to which the drug is
distributed (V = Vc + V +V ). Figure 1 shows an
example scheme of a three-compartment model of
propofol. The distinction of individual compartments
entails the need of a mathematical description of the
migration of drug molecules between the compartments and its elimination from the organism. These
processes may be described by means of elimination
(Cl) and distribution (Q) clearance. The clearance refers to the rate of a process and it is defined as the volume from which total elimination or total distribution
of the drug takes place per unit of time. Similarly, rate
constants may be used to describe drug migration,
c
T,1
T,2
T,1
T,2
ss
ss
T,1
T,2
elimination, distribution or redistribution. Likewise
clearance, they refer to the rate of a process and are
defined as the quotient of the corresponding clearance
and compartment volume. The rate constant is inseparable from the biological half-life, which provides information about the time necessary for concentration
or quantity of the drug to be reduced by half of its initial value. The biological half-lives are very often distinguished in relation to each phase that can be distinguished in a semi-logarithmic diagram. In a threecompartment model, three phases can be observed,
which are named with consecutive letters of the Greek
alphabet (a, b, g, etc.).
With drugs used in anesthesiology, there is a delay
between the effect of the drug and its concentration
observed in the blood. This leads to a hysteresis loop
when the correlation between the drug concentration
in the blood and pharmacological effect is presented
in a diagram (Fig. 2). In order to account for this delay, the presence of a hypothetical compartment, i.e.,
biophase compartment, is postulated. It refers to the
place of effect of the drug (biophase), to which the
drug is distributed and which is in equilibrium with
the drug concentration in the blood. The application
of drug concentrations in the biophase leads to the
achievement of direct dependence between the concentration and therapeutic effect, which usually has
the form of a sigmoid curve described with the Hill
equation (Figs. 1 and 2). The Hill equation is characterized by three parameters: the maximum effect
(E ); the concentration, which leads to the effect
equal to a half of the maximum effect (EC ); and the
max
Compartment
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50
Fig. 1. The schematic diagram of a typical PK/PD model of propofol. It is used
to describe propofol concentration
and anesthetic effect. VC, VT,1, and
VT,2 denote the volume of the central,
slow and fast distribution compartment; Cl, Q1 and Q2 denote the elimination and distribution clearances; ke0
is the distribution rate to the biophase
compartment; Emax denotes the maximum effect; EC50 is the concentration
leading to the half-maximum effect;
and g is the Hill coefficient
Potential pitfalls of propofol target controlled infusion delivery
Agnieszka Bienert et al.
Fig. 2. A typical concentration-time
profile of propofol in the blood and biophase (A), the relationship between
propofol concentration in the blood
and biophase and the anesthetic effect (B), and the resulting time course
of the anesthetic effect (C). The simulation was based on the model
presented in Figure 1 with the following
parameters: Cl – 1.44 l/min; Q1 – 2.25 l/
min; Q2 – 0.92 l/min; VC – 9.3 l; VT,1 –
44.2 l; VT,2 – 266 l; keo – 0.2 min-1; Emax
– 80; g – 3; EC50 – 2.5 mg/l. The infusion
rate and duration was 0.2 mg/min/kg
and 100 min
Hill coefficient which determines the slope of the relationship between the effect and concentration (g).
Time to peak effect (t
) is the pharmacodynamic parameter, which enables prediction how much
time is necessary for a particular hypnotic or opioid
agent to achieve its peak effect after a single dose. For
example, it is about 1–2 minutes for remifentanil and
5–6 minutes for sufentanil. In clinical practice it
means that when a stress-inducing surgical or anesthesiological manipulation is planned, it is recommended to administer sufentanil somewhat sooner
than remifentanil. The time necessary for concentration of the drug in the biophase to achieve its peak
value after administration of a specific dose (t )
does not always correspond to peak effect time, because the relationship between the effect and concentration is sigmoidal (Fig. 2). The plateau phase, i.e.,
further increase in the concentration, does not lead to
intensification of the clinical effect. Moving around
peak effect
peak
the range of supramaximal concentrations, within the
range of the plateau phase, the peak effect can actually be observed immediately after administration of
the drug, although it will not reach its peak concentration in the brain yet, it will be high enough to have its
maximum possible effect. The introduction of the
concept of biophase compartment also contributed to
more precise specification of the volume of distribution used to calculate induction doses of drugs. The
induction dose of the drug is calculated according to
the formula (D = C•V ): it depends on the drug concentration (C) one wants to achieve in a specific volume of distribution (V ). However, the volume of distribution changes over time, initially V is low (equal
to the volume of the central compartment), because
the drug penetrates only into the tissues which are rich
in blood vessels. However, with time it is widely distributed to the deep compartments, which results in
the volume of distribution reaching high values at
ind
d
d
d
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785
steady state and sometimes exceeding volume of the
body. Therefore, the concept of the volume of distribution at the time of peak drug concentration in the
biophase was introduced. The induction dose should
be calculated on the basis of this value as it is more
precise than the volume of the central compartment.
On the other hand, a pharmacokinetic parameter
which is useful in describing the rate of patient’s awakening is context sensitive half-time (CSHT), i.e., the
period of time after which the drug concentration drops
by half after finishing the infusion. This concept was
introduced by Hughes et al. in 1992 and later it was extended by the time necessary for the concentration to
drop by 10, 20 or 30%, because the idea is to characterize the drop in drug concentration to the level corresponding with awakening. Effect-site decrement time
curves, which are widely discussed in literature, describe the time necessary for a particular decrease in
drug concentration after stopping its infusion accounting for the time of infusion [22, 23, 39, 64].
The pharmacokinetic and
pharmacodynamic parameters
of propofol
Propofol is a small lipophilic particle, which strongly
binds to proteins and penetrates into erythrocytes. In
the plasma, more than 98% of propofol is bound,
mainly by albumins, red blood cells, and lipid fractions [21, 29, 35]. The percentage of free fraction depends on the total concentration of propofol in the
blood. For total concentrations under 2 µg/ml an increase in the free fraction was observed along with
a drop in the concentration of propofol. When the total concentration is very low, even as much as 100%
of propofol may be unbound. For concentrations
higher than 2 µg/ml, the free fraction is constant and
equals about 2% [18]. Only unbound drug is responsible for the pharmacological effect: therefore, the nonlinear binding of the drug in the blood may influence
the clinical effect.
After administration of a single dose, the pharmacokinetics of propofol is well described by threecompartment model, with the biological half-lives of
t a = 1.8, t b = 34 and t g = 180 min, respectively
[64]. The elimination half-lives of b and g phases are
relatively long, but the clinical effect of the drug can
0.5,
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0.5,
0.5,
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be observed for a relatively short time. The correlation between the time of infusion and offset of the
drug effect is better described by the CSHT. For propofol the time is shorter than 25 min for an infusion
lasting up to 3 h and it is 50 min for a prolonged infusion
[64]. The following pharmacokinetic parameters for propofol were obtained for surgical patients in multi-center
studies [55], based on the three-compartment model: the
volumes of the central compartment (V ) and the slow
(V ) and fast (V ) distribution compartments were 9.3 l,
44.2 l and 266 l, respectively; The elimination clearance (Cl) and distribution clearances (Q and Q )
were 1.44, 2.25 and 0.92 l/min, respectively, for a 70
kg adult. However, in patients over 70 years old, a linear decrease in propofol elimination clearance was
observed along with their age [55].
The pharmacokinetics of propofol in patients in intensive care units (ICU), who undergo prolonged infusions, is slightly different. Above all, the propofol
volume of distribution at steady state increases. According to the literature, the volume of distribution at
steady state is 23.8 l/kg of body mass for an infusion
lasting 72 h [4]. For a shorter infusion lasting up to 24 h,
the value of 499 l was obtained, i.e., about 7 l/kg for
a 70 kg individual. This is about two or three times
more than for a short infusion during anesthesia [20,
37, 57]. The volume of the central compartment is
about 31 l for an infusion lasting up to 24 h. A similar
value (27.2 l) was obtained in another group of patients for an infusion lasting 98 h on average [9]. Also
the volume of the peripheral compartment for propofol increases during a prolonged infusion and makes
about 801 l [9], as compared with the values of about
113 –158 l obtained during general anesthesia [11,
38]. In different studies the clearance of propofol during a prolonged infusion was 1.57, 2.11 and 2.55 l/min
[5, 9, 36]. The value of propofol clearance for operative procedures is 1.70 l/min [11] – 2.08 l/min [55].
The distribution clearance of propofol during a prolonged infusion is about 2.70 l/min [9]. The terminal
biological half-life of propofol (t g ) depends on the
return of its molecules from the tissues with poor blood
supply. In patients subjected to several-day sedation
with propofol it ranges between 23.5 and 31.3 h [37].
During a prolonged infusion lasting more than three
days, the concentration of triglycerides in the patient’s
plasma must be monitored due to the risk of hypertriglyceridemia [37].
The pharmacokinetic parameters of propofol
change with patient’s age as well: children require
C
T,1
T,2
1
0.5,
2
Potential pitfalls of propofol target controlled infusion delivery
Agnieszka Bienert et al.
Tab. 1. The pharmacokinetic parameters of propofol for infants and children obtained on the basis of the three-compartment model [5, 28, 41,
52, 57]
Kataria et al. [28]
Allegaert et al. [5]
Murat et al. [41]
Saint-Maurice et al. [52]
Adults [57]
53
3–11 y
15–61
0.52
9.7
0.034
9
4–25 days
0.9_3.8
0.34
3.7
0.014
12
1–3 y
8.7–18.9
0.95
8.17
0.049
10
4–7 y
17–24
0.72
10.9
0.031
29
43 (mean)
66 (mean)
0.12
3.4
0.028
Number of patients
Age (range)
Weight (kg, range)
Vc (l/kg)
Vss (l/kg)
Cl (l/min/kg)
Vc – the volume of central compartment, Vss – volume of distribution at steady state, Cl – clearance
higher induction and maintenance doses of propofol
per kg of body mass due to the higher volume of distribution and drug clearance (Tab. 1) [5, 28, 33, 41,
52]. In a geriatric population, the elimination of propofol is slower, which is related mainly to the reduced
hepatic flow and cardiac output. The total clearance
decreases by about 28% in patients over 60 years as
compared with patients younger than 60 [57]. The
volume of the vessel rich compartment and the rate of
drug distribution into that compartment are also reduced. The volume of the central compartment is
about 0.32 l/kg of body mass in patients aged 65–80
years as compared with the value of about 0.40 l/kg of
body mass observed in patients aged 18–35 years
[37]. Thus, the concentration of propofol will change
more rapidly in geriatric patients. Increasing the rate
of infusion of propofol in a 75-year-old patient causes
its concentration in the plasma to rise by about
20–30%, as compared with a younger person. This
fact is the reason why the dose of propofol administered to geriatric patients needs to be reduced by
about 30–75%. In elderly patients, the post-infusion
elimination of the drug is also prolonged. After finishing an infusion lasting one hour, the value of the
CSHT parameter is only slightly different. However,
after four hours of continuous infusion in an 80-yearold patient, it is twice as high as in a 20-year-old [51].
As far as pharmacodynamics is concerned, the value
of EC for loss of consciousness falls by about 50%
between the age of 25 and 75 years (2.35 vs. 1.25 mg/l).
However, greater sensitivity to the hypnotic effect of
propofol is not coupled by the changes in the blood –
effect site equilibration half-life, which remains constant with age (t (k ) = 2.3 min.). The sensitivity to
depressant effect of propofol on blood pressure is also
enhanced in elderly patients. The EC for hypotension after propofol administration equals 2.09 mg/l for
patients aged 70–85 years, whereas for patients aged
20–39 years it reaches the value of about 4.61 mg/l.
Also, the cardiodepressive effect of propofol is slightly
delayed when compared with younger patients: t
(k ) in an 80-year-old patient is about 10.22 min, as
compared with the value of 5.68 min. in a 25-year-old
person [63].
In obese patients (BMI > 35) it is recommended to
convert the induction dose of propofol to the ideal
body mass (IBM), which is calculated for men and
women according to the following formula:
50
0.5
e0
Men: IBM (kg) = 49.9 + 0.89 x (height (cm) – 152.4)
Women: IBM (kg) = 45.4 + 0.89 x (height (cm) – 152.4)
or: IBW (kg) = height (cm) – x, where x = 100 for men
and 105 for women [8].
In spite of its high lipophilicity propofol does not
exhibit a strong tendency to accumulate in extremely
obese patients. Therefore, when maintaining anesthesia, it is possible to base it on the total body weight
(TBW). However, this may lead to higher concentrations of the drug during emergence from anesthesia
and higher hemodynamic instability. Therefore, the
adjustment of maintenance doses to the lean body
mass (LBM) is suggested or applying the formula:
IBW + 0.4 × kg body mass over IBW [8].
50
0.5
e0
Propofol is predominantly metabolized in the liver.
Initially it is oxidized to 1,4-di-isopropylquinol, then
glucuronidation takes place. Propofol and 1,4-diisopropylquinol are coupled with glucuronic acid and
produce corresponding glucuronides: propofol glucuronide, quinol-1-glucuronide and quinol-4-glucu-
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ronide. In vitro studies indicate the involvement of the
enzymes UDP-glucuronosyltransferase, particularly the
isozyme 1A9 (UGT1A9), cytochrome P450 2B6
(CYP2B6), 2C9 (CYP2C9), sulfotransferases (SULT)
and DT-diaphorases (NQO1) [48]. The existence of
extrahepatic metabolism is also taken into consideration. Takata et al. suggested that the organs responsible for its metabolism are the kidneys, small intestine,
brain and lungs, where the kidneys were ascribed the
most significant role [58, 60, 62]. Propofol has high
hepatic extraction ratio. Therefore, there is a correlation between its elimination rate and the cardiac output and hepatic blood flow [45, 62].
Generally, propofol is a safe anesthetic agent.
However, propofol infusion syndrome (PRIS) is a rare
and potentially lethal adverse drug event associated
with high doses (> 4 mg/kg per hour or > 67 µg/kg per
min) and long-term (> 48 h) use of propofol. Also, it
can be observed with lower doses and after shorter
duration of sedation. PRIS is characterized by severe
metabolic acidosis, rhabdomyolysis, hyperkalemia,
lipemia, renal failure, hepatomegaly, and cardiovascular collapse. The physiopathology of PRIS mechanism remains unclear, however, a dysfunction of
mitochondrial respiratory chain could be involved and
potential genetic factor may account. The occurrence
of PRIS may be related to the existence of a genetic
susceptibility, such as an inborn error of mitochondrial fatty acid oxidation [32, 48, 67].
The factors modifying the
pharmacokinetics and effect of propofol
In clinical conditions, numerous factors may change
the pharmacokinetics and end organ effect of propofol. Since propofol significantly binds to various components of the blood, in pathological states, such as
hypoalbuminemia or anemia, an increase in the free
fraction of the drug can be expected. Propofol has
high hepatic extraction ratio: the free fraction is not
compensated by higher clearance and accelerated
elimination. In this situation, the total concentration at
steady state remains unchanged, but the concentration
of the unbound drug increases and its effect becomes
intensified. This may be of clinical importance for
highly protein-bound drugs with narrow therapeutic
indices, such as propofol. The situation is different in
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the case of drugs with low hepatic extraction, where
an increase in the free fraction causes a parallel increase in clearance and decrease in total concentration. As a result, the unbound drug concentration and
the effect of the drug remain unchanged. Approximately a double increase in the propofol free fraction
was noted, with an unchanged total concentration in
patients undergoing the coronary artery bypass graft
surgery as a result of hypoalbuminemia [24]. Considerable changes in the pharmacokinetics of propofol
were also observed in patients qualified to groups
II–IV according to the ASA scale, who had severe
burns accompanied by acute anemia and hypoalbuminemia [66]. They had a higher volume of the central
compartment (48.4 l) in comparison with the control
group (27.6 l) as well as a higher central and peripheral compartment clearance (4.2 l/min 3.6 l/min,
respectively) as compared with the control group of
patients without burns (1.7 l/min and 1.1 l/min, respectively). No definite cause of those changes was
identified, though. It is known that in patients after
a severe, extensive burns, increased cardiac output or
altered levels of different blood components can be
expected for as long as several weeks or even months
[66]. On the other hand, the pharmacokinetics and
pharmacological effect of propofol was not observed
to depend on the composition of plasma, including the
level of proteins, hematocrit, erythrocytes or the level
of erythrocytes in the patients of groups I–III, according to the ASA scale, who underwent surgeries and
whose values of the abovementioned results were contained within the standard limits [11]. In intensive care
units (ICU), patients’ clearance of propofol may depend on the level of triglycerides in the plasma and
body temperature, though studies on the subject are not
unequivocal. One of the reasons for that fact is a relatively small number of patients [9, 29]. In hemorrhagic
shock, the elimination of propofol is slow, whereas the
pharmacological effect is intensified [30, 42].
A significant role in accounting for those changes
is ascribed to the impaired cardiac output [44]. In ICU
patients suffering from reduced myocardial contractility, the clearance was slower by as much as 38% in
comparison with critically ill patients without heart
failure. Simultaneously, the pharmacodynamics of
propofol depended on the severity of the patient’s
state expressed according to the Sequential Organ
Failure Assessment (SOFA) score. As the state of
health deteriorates, smaller doses of propofol were
necessary to obtain the same degree of sedation [45].
Potential pitfalls of propofol target controlled infusion delivery
Agnieszka Bienert et al.
Recently, Wiczling et al. [65] have developed the
PK/PD model of propofol in patients undergoing
abdominal aortic surgery. The authors noted an
increased value of propofol metabolic clearance
(2.64 l/min) coupled with decreased sensitivity to propofol anesthesia. The obtained value of EC was
about 2.19 mg/l, which was in agreement with the
literature values of 1.98 mg/l for ICU patients and
1.84 mg/l for the patients with SOFA score equal 15
[9, 42]. Propofol is also widely used during cancer
surgery. It has been recently demonstrated that neoadjuvant chemotherapy before surgery significantly reduces the EC of propofol for induction of anesthesia
(EC was about 4.11 mg/l in the non-neoadjuvant
group, whereas in the taxol- as well as cyclophosphamide-adriamycin-5-Fu groups they were 2.94
and 2.91 mg/l, respectively) [68]. Further studies on
50
50
50
the pharmacokinetics and pharmacodynamics of propofol are required in this group of patients, because
recent literature data have suggested that anesthetic
drugs may influence the patients’ long-term outcome
after cancer surgery. It was shown on animals that,
contrary to other studied agents, propofol did not
increase the tumor metastasis. Although human data
are more difficult to interpret, due to some beneficial
effects propofol may be expected to be increasingly
used in cancer surgery [58].
The animal research suggests that the time of the
day may be a factor determining the effect of propofol
[10, 14]. That supposition was not confirmed by the
tests on critically ill patients exposed to propofol infusion for a prolonged time [9]. However, it is worth noting that severe disorders in the rhythms of essential
vital signs were observed in ICU patients [7, 9, 43].
Fig. 3. A comparison of the literature
pharmacokinetic models of propofol
(Schnider [53], Bjornsson [12], Schuttler [55], Marsh [34]) for a 40-year-old
male adult of 70 kg and 170 cm. The
following infusion was used for the
simulations: initial dose 2 mg/kg, rate of
infusion 0.2 mg/min/kg and duration of
infusion 200 min. The continuous line
represents typical propofol concentrations, whereas the shaded area represents the range of concentrations
found across all the subjects in the
studied population. The dotted line representing a typical concentration of the
Schnider model is presented for an
easy comparison
Pharmacological Reports, 2012, 64,
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Pharmacokinetic models available in TCI
systems
TCI systems for dosage of propofol have been available since 1997. The first systems included a Diprifusor® microprocessor (Astra Zeneca, UK), programmed on the basis of the Marsh pharmacokinetic
model developed for adult patients. In the beginning,
the dosage was based on the basis of simulated concentration of the drug in the plasma. Then, after introducing parameter ke0, describing the rate at which the
drug enters the biophase, i.e., the brain, the rate of infusion can also be adjusted to the current concentration in the effector tissue. Diprifusor® was meant only
for one propofol preparation – Diprivan. So called
open TCI systems, which are currently used, give
a possibility to program the dosage of various intravenous drugs according to different pharmacokinetic
models. Two open TCI systems are available, i.e.,
Alaris Asena PKTM (Cardinal Health, Alaris Products,
Basingstoke, UK) and Base PrimeaTM (Fresenius,
France). Two models for adults (the Marsh and
Schnider models) and the Kataria and Paedfusor models for children are programmed in the former system.
The Base Primera system offers a choice of two models for adults, the modified Marsh model and the
Schnider model [3]. Figures 3 and 4 show a comparison of the pharmacokinetic models of propofol from
the literature for an adult and for a child, respectively.
An interpretation of those diagrams may be useful in
clinical practice. The expected concentrations of propofol after administration of a specific dose of the
drug to the patient, shown in Figure 4, are lower for
the Kataria model than for the Schnider and Paedfusor
models. Because of this, when using the Kataria
model, in order to achieve the same target concentrations, the infusion pump will administer higher doses
of the drug than the TCI system based on the Paedfusor model.
Fig. 4. A comparison of the literature
pharmacokinetic models of propofol
(Schnider [53], Kataria [28], Paedfusor
[2]) for a 10-year-old male child of
30 kg and 130 cm. The following infusion was used for the simulations: initial dose 2 mg/kg, rate of infusion
0.2 mg/min/kg and duration of infusion
200 min. The continuous line represents typical propofol concentrations,
whereas the shaded area represents
the range of concentrations found
across all the subjects in the studied
population. The dotted line representing a typical concentration of the
Schnider model is presented for an
easy comparison
790
Pharmacological Reports, 2012, 64,
782–795
Potential pitfalls of propofol target controlled infusion delivery
Agnieszka Bienert et al.
Differences between the Marsh and
Schnider models
The models were developed in different investigations and for different populations. Therefore, their
application will lead to certain differences in the suggested rates of infusion of propofol. The differences
will be evident within the first ten minutes in patients
with normal body mass and slight obesity. However,
in patients with severe obesity, two models will provide different infusion rates during the entire period
of anesthesia [3].
The Marsh model was suggested on the basis of research conducted on 3 groups of patients (6 patients in
each); they received three constant infusions of propofol administered at the rates of 3, 6 and 9 mg/kg/h, respectively. No detailed demographic characterization
of the volunteers was published. However, probably
there were few obese and elderly patients in the population. Later, Struys et al. suggested amending the k
value of propofol and that model, known as the Marsh
modified model, is applied in the TCI system of Base
Primea [3, 34].
The Schnider model was suggested on the basis of
investigation conducted on 24 volunteers of both
sexes (11 women and 13 men with the body mass
ranging from 44 to 123 kg and age from 25 to 81
years). The parameters of the model depended on the
patient’s age, total body mass, lean body mass and
height. The lean body mass was calculated on the
basis of the James formula, which works in patients
with slight or moderate obesity, but fails in patients
with severe (BMI > 40) or extreme obesity (BMI >
50) [3, 53, 54].
The data available in the literature do not provide
evidence of the advantage of either model. Most experts think that anesthesiologists should apply the
‘friendlier’ model. With currently available evidence,
in most of the clinical situations, the safest options,
and those most commonly chosen by clinicians, are
either of the Marsh in plasma mode or the Schnider
model in effect-site mode. If the Marsh model is used
in effect-site targeting mode, then it should be used
with the faster k for propofol recommended by
Struys and colleagues (1.2 min) [3]. In contrast to the
Schnider model, the Marsh model does not allow for
the patient’s age, which is a disadvantage. Thus, in
practice when using the Marsh model in elderly patients, the concentrations of propofol in the plasma
e0
e0
will actually be higher than expected, which may lead
to hemodynamic instability. This may speak in favor
of the Schnider model in a geriatric population. Figure 5A shows differences in the values of concentrations of propofol in the plasma obtained for an infusion with the same parameters in a 40-year-old and an
80-year-old patient, but described by means of different pharmacokinetic models. It is evident that the
Marsh model does not allow for differences in age,
because it assumes identical concentrations of the
drug, regardless of the age.
The application of TCI systems to patients with severe and extreme obesity still poses a problem. Clinical experiments with the Marsh model applied to
those patients show that the introduction of the patient’s total body mass leads to hemodynamic instability during the induction of anesthesia. It is related
with the fact that in obese patients the volume of distribution of the central compartment does not change
and patients are overdosed with the induction dose
calculated for the actual body weight. Therefore, it is
recommended to calculate induction doses per ideal
or fat-free body mass. The situation is even more
complicated by the fact that the demand for propofol
during the maintenance of anesthesia increases proportionally to obesity, so maintenance doses should
rather be adjusted to the total body mass. Thus, the
anesthesiologist faces a difficult problem which body
mass should actually be entered to the TCI system.
Many follow the recommendations suggested by
Servin et al. [56] and calculate the body mass on the
basis of the following formula:
IBM + 0.4 (TBW – IBM).
However, this formula seems to work only during
the first 20–40 min of anesthesia and then the concentrations remain lower than assumed. Figure 5B shows
differences in the values of concentrations of propofol
in the plasma for an infusion with the same parameters, in patients with the body mass of 70 and 120 kg,
simulated with the application of different PK models.
As can be seen, the Marsh model does not allow for
differences in the pharmacokinetics of propofol in
obese patients. In a study published in 2010, Cortinez
et al. [17] suggested a pharmacokinetic model of propofol, which characterized the dependence of the
pharmacokinetics of propofol on the patient’s total
body mass. The model was supposed to adjust the
dosage of propofol to obese patients better than the
James formula suggested in the Schnider model. The
Pharmacological Reports, 2012, 64,
782–795
791
Fig. 5. The influence of age (A) and
body mass (B) on the propofol pharmacokinetics on the basis of selected
literature models (Schnider [53],
Schuttler [55], Marsh [34]). The simulations are for a (A) 40-year-old (continuous line) and 80-year-old (dotted
line) male adult of 70 kg and 170 cm;
and for (B) a 40-year-old male adult of
70 kg (continuous line) or 120 kg (dotted line) and 170 cm. The following
infusion was used for the simulations:
initial dose 2 mg/kg, rate of infusion
0.2 mg/min/kg and duration of infusion
200 min
authors suggest applying this model in TCI systems.
At present special care is recommended when applying TCI systems to obese patients [3].
Although we may realize the limitations resulting
from TCI systems, simultaneously we must remember
that even if we ensured perfect precision, which was
close to a direct measurement of the drug concentration in the patient’s artery, their reaction to the drug
may still be different from our expectations. It is not
only individual variability in the PK parameters of the
anesthetic that is a clinical problem, but it is also the
pharmacodynamic variability, i.e., different response
to the drug, where its concentration is known and expected. This is a separate issue.
Pediatric models
In order to make children sleep during anesthesia, inhaled drugs are mainly applied. However, recent stud792
Pharmacological Reports, 2012, 64,
782–795
ies show that TIVA with propofol may be a good alternative to children [15, 53, 54, 61]. Alaris® company offers two pharmacokinetic models for children:
Paedfusor and Kataria [2, 28, 33]. Both have been
tested in clinical conditions. The minimum age limit
for the Paedfusor model is 1 year, where the child’s
lowest permissible body mass is 5 kg. The Kataria
model may be applied to children aged over 3 years,
with the minimum body mass of 15 kg. Absalom et al.
[1] estimated the mean error of the model programmed in the Paedfusor, which was 4.1%. The
value was lower than the one for the Dipriphusor in
adults [59]. The Paedfusor was validated in clinical
conditions in a group of 29 children aged 1–9 years,
qualified for groups II and III according to the ASA
score, who underwent cardiac surgeries [1]. The precision of Paedfusor deteriorates when the system does
not dose propofol, e.g., after stopping the pump or immediately after reducing the target concentration. In
those periods, the drug concentration measured in the
plasma was on average by 20% higher than the concentration simulated by the TCI pump [1]. The avail-
Potential pitfalls of propofol target controlled infusion delivery
Agnieszka Bienert et al.
able children pharmacokinetic models do not enable
the dosage of propofol on the basis of effector
concentration, because the value of ke0 parameter in
this population has not been appropriately estimated
[16, 33].
The dosage regimen of propofol 10-8-6 suggested to
adults [50], which ensures keeping maintenance concentrations at 3 µg/ml, leads to subtherapeutic concentrations in children. It is the result of higher values of
the central compartment volume and clearance observed in pediatric population (Tab. 1). McFarlan et
al. [36] suggested a simple scheme of manual dosage
of propofol to children.
We must not forget the fact that the pharmacokinetic parameters of propofol change dynamically with
age and children aged 2 and 12 years cannot be
treated in the same way. Besides, high variability of
the PK and PD of drugs can be observed in this population. As propofol anesthesia applied to children becomes more popular, further research concerning optimal dosage of the drug to this population of patients
can be expected. The studies by Rigouzzo et al. published in 2010 proved that in children aged between
6 and 12 years the Schnider model, which is recommended to adults, may be more useful than classic pediatric models [49].
Summary
In our opinion the problems presented above and the
related areas of doubt concerning the appropriate selection of the system of TCI technologies in different
groups of patients should indirectly increase alertness
during TIVA. This applies especially to the group of
patients who are at risk of perioperative complications
resulting from the physical state of classes III and IV
according to the ASA and to the group of patients who
are subjected to a one-time infusion of neuromuscular
blocking drugs despite the monitoring of the neuromuscular block. The continuous broadening and updating of the knowledge of clinical pharmacology of
propofol may be an important extension of practical
skills of both the clinical pharmacist and anesthesiologist. They are key people in the chain of safety links
implemented according to the rule popularized in the
Jackson Reason’s ‘Swiss cheese’ model [45].
Acknowledgment:
One of the authors (Pawe³ Wiczling) was supported by a grant
from Iceland, Liechtenstein and Norway through the EEA Financial
Mechanism via Homing Program from the Foundation for Polish
Science.
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Received: November 10, 2011; in the revised form: March 22, 2012;
accepted: April 5, 2012.
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