Download TCI: TOOL OR TOY

22 March 2013
N0.10
TCI: Tool or Toy?
K Purchase
Commentator: G Jones
Moderator: C Rout
Discipline of Anaesthetics
CONTENTS
TCI: TOOL OR TOY.............................................................................................. 3
OBJECTIVES ....................................................................................................... 3
INTRODUCTION ................................................................................................... 4
THE BASICS ........................................................................................................ 4
THE DETAIL EXPLORED..................................................................................... 5
EXTREMES of POPULATION ............................................................................. 9
CURRENT CONTROVERSIES ........................................................................... 13
IMPROVING THE TOOL ..................................................................................... 18
ADVANTAGES AND COST EFFECTIVENESS OF TCI ..................................... 21
CONCLUSION .................................................................................................... 24
COMMENTARY .................................................................................................. 25
REFERENCES.................................................................................................... 27
Page 2 of 29
TCI: TOOL OR TOY
OBJECTIVES



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To briefly discuss the basics of target controlled infusions
To illuminate the less evident differences between the models
To discuss the current controversies surrounding TCI
To explore current research in refining TCI
Page 3 of 29
INTRODUCTION
The idea of intravenous drugs has been around for centuries and opium has been
used by way of this method since 1655. In the 1930’s the first intravenous
induction was performed.(32) The advent of propofol in 1977 opened up the door
for not only the induction of anaesthesia by intravenous drugs but also the
maintenance. The discovery of shorter acting opioids in the last decade and
advances in microprocessor technology has flagged the way for the widespread
use of computer controlled drug delivery or as we know it, Target Controlled
Infusion (TCI).
Have these discoveries and advances added a tool or a toy to our toolbox?
History
In 1968 Kruger-Thiemer described the principle of achieving a steady-state blood
concentration of a drug by means of the two compartment model.(32) Over the
years this concept was advanced further, which finally led to the development of
the first computer assisted total intravenous anaesthesia system. Since then the
first TCI system to be made available commercially, the Diprifusor, was released
in 1996.
The expiration of propofol’s patents led to the availability of open TCI systems in
2003. These open systems contain numerous pharmacokinetic models and allow
for the infusion of various drugs including opioids.
THE BASICS
TCI is a computer driven infusion and controlled infusion which aims to maintain a
required drug concentration in a body compartment or tissue of interest. (1) Initially
this compartment was the blood or plasma level based on pharmacokinetic (PK)
models.
In simple terms, by using a mathematical model derived from pharmacokinetic
data, a computer continuously calculates the expected drug concentration in the
target compartment and administers a “BET” (bolus, elimination, transfer)
regimen. Pump speeds typically adjust at 10-second intervals.(2) Newer models
and devices now include pharmacodynamic (PD) data to target effect site
concentrations, i.e. the brain (3)
In all this lies the brilliance but the devil is in the detail.
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THE DETAIL EXPLORED
TCI models are derived from studies in healthy volunteers and may not be
uniformly applicable to all situations or even all populations. Whether or not these
models sufficiently address the individual patient’s requirements is yet to be
determined.(4)
The Marsh model was directly adapted from the Gepts three-compartment model.
This study involved 18 patients. Despite full details of this study not being
published, it appears that it included few elderly or obese patients. Over the years,
some adjustments were made to this model, several of them never published in
peer reviewed journals.
The Schnider model was derived from a combined pharmacokinetic and dynamic
study that involved 24 volunteers with a wider spectrum of demographics.(5)
Early PK models focussed on the plasma concentration as the target. It soon
became evident that there is a lag-time between plasma concentration and the
effect- site concentration. This led to the introduction of the concept of “effect site”
targeting.
Effect site concentration cannot be measured for IV agents. The plasma\effectsite equilibration constant is mathematically estimated and represented by keo.
Alternatively, keo can be estimated by recording a measure of clinical effect, such
as evoked EEG parameters, and then mathematically generating a value for keo.(5)
Thus, keo is the equilibration rate constant between plasma and effect-site. In other
words, the time it takes the plasma and effect site concentration to reach
equilibrium or the rate at which the drug enters the brain.(4)
This makes it possible to incorporate pharmacodynamics (PD) in models.
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Figure 1: The three compartment model with effect site
V3
V1
(6)
V2
From: Paediatric anaesthesia: 2010;20(3):233–9 – the mistakes are theirs (V2
should read “rapid”, not “slow” – CCR)
A brief description of the common models
With the Marsh model, all the compartment volumes (V1-V3) are proportional to
weight and rate constants are fixed. In the Schnider model, V1 and V3 are fixed
with V2 influenced only by age (smaller with increase in age).(5)
This explains the important difference between the two models. The biggest
variance between the models can be appreciated during the first 10 minutes of the
infusion.
The Marsh model
The estimated plasma concentration is linearly related to weight. Rate of transfer
to different compartments is the same for all patients and weight only influences
the size of the compartments. V1 is directly related to weight and therefore the
initial dose and estimation of plasma concentration will be much higher (compared
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Figure 2: Adult Propofol models (5)
to the Schnider model).
This translates to a larger initial bolus, larger bolus with each target adjustment
and rapid clinical effect, a desirable effect in a young fit patient, but not so in the
elderly or critically ill patient. (32)
Due to weight being the only covariate, the plasma concentration in the elderly is
known to be underestimated. It does not take into account the pharmacodynamic
sensitivity of this age group.(5)
The Marsh model has two alternatives to the classic plasma target model that can
target effect site. The difference is in the keo rate. This rate will affect the plasma
concentration. A slower keo (a lower rate constant) requires a higher plasma
concentration to drive the drug into the effect site.(32)
In each of the two modified models, this keo value is respectively the same for all
patients. The modified Marsh model uses a somewhat faster k eo, but this value is
still considerable slower than the Schnider value. In other words, with the modified
Marsh model a larger total amount of propofol will be infused.
The Schnider model
This model estimates the same plasma concentration for all patients (the volumes
of V1 and V3 are equal for all patients) but the rate of transfer after the peak
plasma concentration is dependent on age (transfer to V2). The covariates include
sex, age weight, lean body mass and length.(7)
This implies that if used in the plasma target mode, the same initial bolus dose will
be given to all patients regardless of any covariate.
If used in effect target mode, a concept of “plasma concentration overshoot” is
implemented. This overshoot is in the range of 300% and is used to create the
gradient needed for effect site concentration.(5) In effect-site targeting the Schnider
model determines a keo specific for each patient. Thus, it creates less overshoot
and undershoot of plasma concentrations around the effect site concentration.(32)
What this transforms to in practice is cumulatively the largest total dose of
propofol will be given by the Marsh model in effect-site targeting mode, followed
by the Marsh model in plasma targeting mode, then the Schnider model in effectsite targeting mode, and lastly the lowest dose will be given by the Schnider
model in plasma targeting mode.(5)
When the Marsh model is used the larger initial bolus results in more rapid clinical
effect and may be associated with profound adverse effects. The Schnider model
has a slower onset of clinical effect for a given target concentration.(32)
Despite all this, current data do not show superiority of any one model. The
recommendations include that the familiar model should be the first choice. If one
chooses to use a different model, a clear understanding of the differences and
limitations is needed.
The majority of experts agree that if the Marsh model is used it should be in
plasma target mode and Schnider in the effect-site targeting mode.(5, 7) Some
authors feel that although not perfect, the Schnider model is the recommended
method,(7) partcularly in the elderly or frail patient.
Opioid models
The Minto model for Remifentanil came from a heterogeneous population of 65
men and women aged between 20 and 85 years. Formal PK and PD studies were
done to derive a value for keo that is adjusted for age.(33) The argument to use this
model in effect-site targeting is not compelling. In plasma targeting, equilibration
between blood and effect site is complete within 5 minutes. When targeting effectsite, the infusion system is able to choose very high plasma concentrations to
achieve the desired over shoot. If the keo is not limited, this can cause adverse
effects.
EXTREMES of POPULATION
All this makes perfect sense for the fit adult conforming to the researched PK
models. How applicable is this to the extremes, such as the very old, the morbidly
obese or the very young?
Geriatric:
The altered PK and PD of the geriatric population are well described. The volume
of the central compartment is about 0.32 l/kg of body mass in patients aged 65–80
years as compared with approximately 0.40 l/kg of body mass observed in
patients aged 18–35 years.(8) Thus the concentration of propofol will change more
rapidly in geriatric patients.
Increasing the rate of a propofol infusion in a 75 year old patient causes its
concentration in the plasma to rise by about 20–30%, as compared with a younger
person. As far as pharmacodynamics is concerned, EC50 (loss of consciousness)
for propofol decreases by approximately 50% from age 25 years to age 75 years.
(4)
A model that does not take these variables into consideration can make for a
very instable anaesthetic.
Age is a covariate in the Schnider but not in the Marsh model. Each bolus dose
and adjustment to target concentration will be made taking age into account. This
makes the model more suitable for the elderly.(4,5)
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Morbidly obese:
The Schnider and Minto model both use the James formula in calculating Lean
body mass (LBM).
Male: LBM=1.1 X weight-128 X (weight/height) 2
Female: LBM=1.07 X weight-148 X (weight/height) 2
This formula is accurate up to a BMI of 42 kg/m2 for males and 37 kg/m2 for
females; thereafter an increase in weight causes a paradoxical decrease in LBM.
As Total Body Weight (TBW) increases, to a BMI >40 kg/m2 LBM decreases and
in the super obese can actually become negative!(9)
Figure 3: Relationship between body weight and lean body mass(5)
British journal of anaesthesia. 2009 Jul :103(1):26–37
This directly affects the calculation for metabolic elimination (k10). This means that
with a BMI> 42 kg/m2 the infusion rate required to replace the estimated k10,
increases dramatically. The problem is that physiologically clearance is linearly
related to LBW not TBW.(10)
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A recent meta-analysis states that LBW with an allometric (see below) exponent
may be most suitable for describing an increase in clearance with increasing body
size, as it accounts for both body composition and allometric scaling principles
related to differences in metabolic rates with regard to size.(11)
Since the James formula has a fundamental flaw in calculating LBM, dosing
inevitably will be variable in the morbidly obese patient.
In accordance with the Schnider formulas (refer to figure 2), k10 is directly
proportional to TBW and indirectly proportional to LBM. LBM therefore modulates
the effect of an increasing TBW on clearance (k10)
Figure 4: Clearance of propofol predicted by various models(12)
Anesthesia and analgesia:2011 Jul;113(1):1–3
This flaw results in very high clearance initially and therefore would, up to a point,
overdose the morbidly obese patient. When the threshold is reached, a 180kg
patient will get less Propofol than a 120kg patient. Due to this yet to be corrected
flaw many devices have a safety mechanism that prevents the user from inserting
a BMI>42 kg/m2.(5)
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In the Marsh model the compartment volumes are proportional to weight.
Therefore, if based on TBW, the obese patient will receive a very large dose at
induction. The problem is that induction requirements are more closely related to
LBM (the volume of distribution of the central compartment does not change
proportional to weight) and maintenance requirements are related to TBW. As a
result, controversy still exists as to what weight to use with the Marsh model.(5)
Some use a weight according to a formula proposed by Servin(13)
Input weight=IBW+0.4x(TBW–IBW)
However after 20-40 minutes this model loses accuracy and overestimates the
desired target concentration(4) and it shows significant bias between predicted and
measured plasma propofol concentrations in morbidly obese patients.(14) This
formula also utilizes Ideal Body Weight (IBW), another point of contention. A
number of nomograms and formulas have been proposed, none of which is
perfect. All this adds to the complexity of the issue.
Currently there are no clear guidelines as to how to use TCI in obese patients and
the only recommendations are special care and knowledge of the limitations of
each model.(4,5,7)
Children:
TCI has yet to gain popularity for use in the paediatric population. The models
available currently all only use weight as a covariate and show wide interindividual variability. Appropriate pharmacodynamic parameters are still being
debated in children and therefore there are currently no models that can target the
effect-site.(6)
In 1991 Marsh et al studied the PK model that they used in adults in 20 children.
The model consistently over-predicted the target concentration. Bolus dose
requirements were 50% greater and maintenance doses 25% greater than those
of the original adult model. The new model was tested prospectively in 10 children
and incorporated these findings in the Marsh paediatric model that has been
validated for children ages 1-9 years.(6)
The Paedfusor, developed by Absalom et al in 1998, has lower limits of age 1year
and weight 5kg.(4) The central compartment volume and clearance have a nonlinear correlation with weight, and the size of the central compartment is rather
large compared to the Marsh paediatric model.(6) The model deteriorates in
precision when the infusion is stopped i.e. with any adjustment to the target level.
During this period it can under-predict by up to 20%. The accuracy of the
Paedfusor system has been prospectively evaluated by Absalom et al.(15) in 29
children aged 1 to 15 years undergoing scheduled cardiac procedures.(6)
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The Kataria model is derived from more than 600 arterial samples taken from 53
children during induction, maintenance and recovery of anaesthesia and
incorporated various covariates. The most significant covariate was found to be
weight. Compartment volumes are a linear function of weight whereas rate of
transfer is fixed.
To date there have been no peer-reviewed publications addressing the predictive
performance of the model (6) although it has been validated for children older than
3 years and above 15 kg.(7)
A recent review in 2010(6) compared the above models with the Schnider model
for propofol in paediatric patients and found that the Schnider model performed
well when used in children over the age of 5 years. The conclusion was that,
whatever the model, a pharmacodynamic feedback such as the bispectral index
(BIS monitor) could be useful to address the inter-individual variability in the
paediatric population.(16)
CURRENT CONTROVERSIES
Mathematics of PK/PD models:
It must be remembered that all PK\PD models are mathematically derived and
assume that a drug is administered into a central compartment, from which it is
eliminated. Drug is then distributed into a rapidly equilibrating peripheral
compartment and more slowly into a third compartment. While the mathematical
assumption that drug added to the central compartment is instantaneously and
completely mixed within the arterial circulation works well for this type of
modelling, it does not relate to physiological reality.(7)
Equilibration actually takes 30 to 45 minutes and the fact that all PK models ignore
this time period has been shown to measurably affect the performance of TCI
pumps.(17)
Applying the models to people outside the study population can be difficult and
has led to confusion and controversy amongst anaesthetists and suppliers alike.
The obese patient has been discussed. The Marsh model has been tried in obese
patients with some degree of success, but in reality it is less than satisfactory. The
Schnider model cannot be applied to morbidly obese patients, because TCI pump
software calculates LBM according to the (now out-dated) James equations,
resulting in excessively rapid infusion rates. Presently, approved TCI pumps do
not permit usage in patients younger than 14-16 years or with a BMI that is
greater than a certain value (e.g. males: BMl > 42 kg/m2;females :BMl >
37kg/m2)(9)
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Figure 5: Relationship of TBW and LBM according to Janmahasatian formula
(5)
British journal of Anaesthesia: 2009 Jul :103(1):26–37
It is generally agreed that dosing according to scales linearly related to TBW leads
to over-dosing of the obese and under-dosing of paediatric patients. Both the
Marsh and Kataria models employ linear dosing.
Two proposed solutions to the controversies surrounding the PK/PD models
include allometric based PK models and incorporating the Janmahasatian Lean
Body Weight formula. There has been some speculation that substituting the
James formula with the Janmahasatian formula would result in a model that is
more accurate and more specifically in the morbid obese patient.(9)
Janmahasatian formula:
Male = [9270 x weight (kg)] / [6680+216 x BMI]
Female = [9270 x weight (kg)] / [8780+244 x BMI]
Using this formula shows a distinct improvement concerning clearance, the main
criticism of the Schnider model.
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Figure 6 : Graph of systematic clearance using two different methods of
calculating LBM(9)
Clinical pharmacokinetics: 2012 Mar 1;51(3):137–45
Allometry is the study the relationship of body size to anatomy, physiology and
ultimately behaviour.(10)
If an object increases in size while retaining its shape (i.e. grows isometrically) its
surface area and volume (and therefore its weight) increase exponentially in
proportion to its increased length, but at different rates. Simply put, as length
increases, weight increases more rapidly than does surface area.(9) Allometric
scaling can be useful in extrapolating the PK principles of various animal species
to humans. Using this knowledge and some complex mathematics, PK models
based on allometric equations have been studied. Increasing evidence suggests
that the PK parameters of propofol can be scaled in this way.
Examination of the literature suggests that allometrically scaled PK parameter sets
may be useful to a wide range of patients including the morbidly obese and
children.(9) It is suggested that if TCI models used improved equations
(Janmahasatian formula) to calculate LBM, the Schnider model would deliver
similar amounts of propofol to morbidly obese patients to the allometrically scaled
PK parameter sets. (9) The suggestion is that both these interventions would
improve the accuracy of TCI pumps.
Currently both these proposals are only being discussed in the literature and have
not been implemented in available TCI devices.
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TCI System performance:
Four parameters were defined by Varevel et al. in 1992 and are still used today in
the assessment of TCI performance; all of these parameters are based on the
Percentage Performance Error (PE).(18)
The Median Absolute Performance Error (MDAPE) is the median PE of the TCI
system and is a measure of accuracy. It is an indication of the accuracy of the
predicted concentration to the measured concentration. A MDAPE of 15% would
mean that half the predictions would be within 15% or closer to the targeted value
and half would be outside that range.
The Median Prediction Error (MDPE) is a measure of the overall bias of the
predictions; it is an indication of degree of systematic over-shooting or undershooting of the target concentration.
Divergence and wobble are indicators of how TCI systems perform over time;
divergences reflects a change in accuracy, and wobble the variability in
performance over time. These parameters are of importance when TCI is used for
an extended time.
The four TCI performance parameters are calculated for individual subjects and
then summarized across an entire population.(17)
A substantial amount of research has been done and is still being done to
evaluate the accuracy of the different models. A recent comparison of 4 propofol
models (including Marsh and Schnider) showed similar MDPE and MDAPE values
in all models during TCI simulations.(7) Similiiar findings were seen by Schüttler et
al.(19)
The typical quoted values for all models range between MDAPE (prediction error)
from 15-30% and MDPE (bias) 3-20%.(17) This can be seen in perspective when
compared to the accuracy of end-tidal concentrations, which have been shown to
over-predict the arterial concentration by 20%. (32)
Interpretation of models:
A universal problem of all PK models is the extrapolation to populations beyond
those investigated in the original study.(20) In other words, external validation is
lacking.
In a review published in 2011(21) the author asks the question whether North
America or Canada are missing out due to the fact that TCI has not been
approved by the FDA in these countries.
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The concerns by the FDA included:
 important health implications,
 significant incremental risk of anaesthetic controllers (not elaborated on)
 concerns that the use of high-level language, general-purpose computers,
and complex operating systems results in products that are too elaborate for
the product developer to verify entirely
 hesitation to accept the extensive literature supporting the clinical use of TCI
on the basis that published reports emphasize positive outcomes.
The author questions the validity of a TCI model applied to a population other than
the studied population (Europeans). He quotes a Chinese study(22) from 2011 that
compared the predicted plasma concentration (Cp) in 30 Chinese people to 30
Austrian people. The Cp was fitted against a bispectral index spectroscopy (BIS)
value. The conclusion was that Chinese patients in China lost consciousness
faster and at a lower estimated plasma concentration than Caucasians in Austria.
This and other similar studies highlight the point that the current PK models have
not been validated in other populations.
However, whether the patient is Chinese or Austrian, the dosing regimen required
to attain the target drug concentration remains the same for all patients of the
same sex with similar age, weight, and height. To map out geographical PK/PD
model is a daunting and unrealistic task.(21) TCI does not create or enhance
variability; this is a function of the biology, not the technology.
Whether or not the clinician uses a TCI device, the task is to administer more drug
if the patient has had too little and to administer less drug if the patient has had
too much. This task can be accomplished by changing the infusion rate manually
as required, by targeting a hypothetical concentration as is done by TCI ,or by
adjusting the volatile concentration.(21)
The above highlights the PD concerns that surround the use of TCI and might
support the use of awareness or depth of anaesthesia monitors to address this
issue.
The concept of inter-patient variability precluding safe use of TCI devices has
been made.
Hu et al.(23) argue that TCI decreases rather than increases biological variability
by firstly incorporating patient covariates in the PK models. It is possible that in the
future pharmacogenetic covariates could also be incorporated in the models.
Secondly, TCI devices inherently understand the accumulation of the drug in
peripheral tissue. This incorporates mathematic equations that most of us are
unable to solve, even with calculators. Therefore, TCI devices achieve a more
predictable relationship between drug administration rate and drug effect than is
possible with conventional infusions.(17)
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IMPROVING THE TOOL
Current TCI devices are still “open loop systems”, that is, there is no feedback
control from the patient to the system.
There is no capability outside the research setting to measure the target
concentration, nor do we have the capability to measure the concentration of drug
that is infused. The amounts displayed on the device are all estimates based on
the PK\PD model, time and amount infused. This assumes that the pump is
performing optimally, that the drug is being delivered into the system, and the
correct data have been entered into the device.
Therefore there is a burden on the anaesthetist to not only be extra vigilant
regarding the physical workings of the pump but also to understand the
appropriateness of the PK model chosen for the individual patient.
Volatile anaesthetics use measured end-tidal concentrations as an estimate of
effect-site concentration and would therefore appear more accurate than IV
agents for which there is no real-time measurement.
However, MAC values are MAC50 values and, like the PK parameters of TCI, are
based upon a sample mean. The time-lag effects for inhaled agents are similar to
those between plasma and effect-site for propofol or remifentanil, with half-lives
between 2 and 4 minutes. This means that a change in end-tidal concentration will
take 5-10 minutes to be fully reflected at the effect site.(3)
Most anaesthetists are comfortable with the values and concept of different MAC
values for various agents and clinical situations and how they interact with other
drugs.
There are numerous recommendations concerning adjusting concentrations to be
targeted during TCI. These include values for premedicated and un-premedicated
patients, for incision and for older patients.
It’s a daunting task and it would seem that most anaesthetists are still more
comfortable with the familiar MAC values than target concentration values. For the
anaesthetist unfamiliar with TCI this implies invariably under-dosing or overdosing of the patient.
A substantial amount of work is being done in an attempt to “close the loop”. The
first is by incorporating an effect monitor, for example a BIS monitor, with
continuous feedback to the TCI pump. This information would then be interpreted
and the pump will adjust accordingly and deliver a more precise dose.(24)
A second option is the concept of measuring end-tidal propofol, which is exhaled
during anaesthesia and can be measured using mass spectrometry. After i.v.
Page 18 of 29
administration it equilibrates between blood and lung and between blood and its
effect-site in the brain. Using this knowledge, Hornuss et al.(25) came to the
conclusion that real-time monitoring of exhaled propofol reflects changes in
propofol effect-site concentration. This measurement will then give feedback to the
system and infusion rate can be adjusted accordingly. Although this is very
innovative it still doesn’t fully address the issue of PD variability.
A further option being explored is adding a “clinical observation” into the loop.
Mandel et al.(26) proposes a control system that incorporates the operator's
observation of loss of responsiveness to determine specific patient sensitivity to
propofol. The hypothesis is that a control system would reduce the impact of
pharmacokinetic parameter error and uncertainty in sensitivity to PD response. A
computer simulation was used to generate a population of 10,000 patients with
randomly distributed PK parameters and sensitivity to propofol. They found that
their novel approach reduced the variability in achieving the specified target by a
factor of 3.1 compared with TCI.
This system suggests that the impact of biological variability can be reduced by
including the operator in the control loop. The utility of this approach in clinical
practice will require further evaluation.
Figure 7: Components of typical closed drug delivery system(23)
Anesthesiology. 2005;102(3):639–45
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Reports from several research groups indicate that closed loop systems are not
only feasible but may have distinct advantages over open loop systems.(24)
Some of these proposed advantages include: (23)
 More consistent drug administration
 Less inter-patient variability
 Less over- and under-dosing
 Faster control of unexpected arousal (less awareness by patient during
surgery)
 Smaller quantities of drug used
 Faster recovery of the patient
 Better haemodynamic control
 Less hypotension during induction of anaesthesia
Concerns regarding multiple drug infusions are also being addressed in the
research arena with two devices on the forefront. Drug interactions have a
significant influence on various anaesthetic end-points. New devices incorporating
these interactions are the latest step in research. They provide forward estimates
of drug concentrations based on current settings, and they have the potential to
influence drug dosing at all stages of anaesthesia. Two such devices, SmartPilot
View® and Navigator Suite®, are currently being researched for clinical
application(27)
Awareness monitoring
If closing the loop is still only a future option, an attractive alternative seems to be
to add brain monitoring into the process. This could at least act as a bridge
between the current open system and a completely closed system.
Although routine use of brain function monitor, e.g. a BIS monitor, will in theory,
bridge the gap in TCI, it is not an ASA recommendation. It could be argued that
they do not need recommendations specific to TCI due to the lack of approval by
the FDA. However, North Americans and Canadians do use TIVA and, if it is
assumed that TIVA creates greater variability then TCI, it would seem prudent for
them to create such guidelines if deemed necessary.
A review by Manberg et al.(24) mention that intra- venous anaesthesia appears to
carry a greater risk for awareness than does inhalation anaesthesia, perhaps
because practitioners can routinely monitor exhaled anaesthetic gas and alarms
can be set for low concentrations, whereas neither of those practices is possible
with the use of intravenous drugs.
Also blood concentrations are not measured in real time with total intravenous
anaesthesia, and infiltration of intravenous catheters, disconnections or dosage
miscalculations may result in inadequate anaesthesia.
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They suggest the routine use of brain monitoring if intra-venous anaesthesia is
used for maintenance of anaesthesia. Once again, it should be noted that this is
not endorsed by the ASA. They agree that using TCI is one of various risk factors
for awareness but certainly not the only consideration.(28)
ASA recommendations include intraoperative monitoring of depth of anaesthesia,
to minimize the occurrence of awareness that should include multiple modalities,
including clinical techniques (e.g., ECG, blood pressure, HR, end-tidal anaesthetic
gas analyser, and capnography). Brain function monitoring is not routinely
indicated for patients undergoing general anaesthesia, either to reduce the
frequency of intraoperative awareness or to monitor depth of anaesthesia. The
decision to use a brain function monitor should be made on a case-by-case basis
by the individual practitioner of selected patients.(28)
The superiority of the BIS monitor is not unanimously agreed. A Cochrane review
states that BIS-guided anaesthesia could reduce the risk of intraoperative recall
among surgical patients with high risk of awareness in studies using clinical signs
as standard practice but that this effect could not be demonstrated in studies
using end tidal anaesthetic gas concentrations as standard practice. (29)
Brain function monitors are dedicated to the assessment of the effects of
anaesthetics on the brain and provide information that correlates with some depth
of anaesthesia indicators, such as plasma concentrations of certain anaesthetics
(e.g. propofol).(28) In the context of TCI, a brain function monitor will be able to
indicate the effect of the hypnotic on that specific patient.
These and the issues related to PD variability mentioned earlier have led to the
appeal to incorporate the advantages offered by continuous anaesthetic effect
monitoring into either an open- or closed-loop system. This would enhance the
precision as well as the safety of infusion devises.(24)
It may be difficult to advocate the routine use of TCI without brain function
monitoring particularly in comparison to volatiles with agent monitoring. Monitoring
of some sort allows us to know the drug is delivered and facilitates titration.
ADVANTAGES AND COST EFFECTIVENESS OF TCI
The uses and proposed advantages of TCI are well known to most of us.(2),(26)
 Separates provision of anaesthesia from ventilation
 Reduced incidence of postoperative nausea and vomiting
 Reduced atmospheric pollution
 Rapid, clear-headed recovery
 Easily titrated
 Safe in malignant hyperthermia
 Preservation of hypoxic pulmonary vasoconstriction
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






Reduction in intra-cerebral pressure
Little evidence of organ toxicity
Elimination of calculation errors
Compensation for any interruption to the infusion
Easy to assess the relationship between drug concentration and effect
Display of effect-site concentrations
Prediction of time to recovery (context-sensitive decrement time)
The issue of cost is not as clear-cut as previously thought. The issue goes far
beyond a simple cost comparison between propofol and the volatile agents. For
example, proposed advantages of intra-venous anaesthesia include changes in
cancer and long term neurological outcomes. Without full economic analysis of all
outcome measures, we do not have the answer to provide a definitive answer. (31)
Whether or not TCI improves on manual infusions is a long-standing debate and
far from over. A Cochrane review evaluating TCI versus manual infusions was
unable to make firm recommendations about the use of TCI versus manual
infusions in clinical anaesthetic practice.(32) The main reason for this was that most
studies reviewed were, by their definitions, small and of poor quality. It can be said
that we need more well-designed studies to evaluate outcome benefits.
TCI USE IN SEDATION
Procedures are being performed increasingly frequently under sedation in
outpatient environments rather than in the operating theatre under a general
anaesthetic. This is particularly relevant in dental, radiological and endoscopic
procedures where the surgeon requires the patient to maintain their own airway,
breathe spontaneously and be able to tolerate episodes of painful stimulation with
minimal discomfort post operatively allowing for early discharge home. (34)
Propofol is still the most popular anaesthetic agent for TCI and PCS (patient
controlled sedation) due to its predictability, low incidence of adverse effects and
low context sensitivity. However, when used alone, there remains an increased
risk of apnoea and movement with painful stimuli.(34)
Accordingly, more research will be conducted in making sedation safer for use by
operators without an anaesthetic background. Two main areas of further research
are firstly the combination of propofol with adjuvants such as opioids (remifentanil,
sufentanil and alfentanil) and ketamine, and secondly modification of TCI systems
such as Patient Controlled Sedation – first described by Rudkin in 1991.(35) PCS
combines TCI with a patient-demand function. A target plasma or effect-site
concentration is determined using the usual parameters such as age, sex and
BMI.
Page 22 of 29
This target site concentration is altered based on the frequency of the patient’s
button pressing. When the patient presses the button, the target is increased. The
converse occurs when no button is pressed for a certain period. (34)
A new proprietary system Sedasys® (Ethicon Endo Surgery, Inc., Cincinnati, OH,
USA) incorporating comprehensive patient monitoring and software has been
developed for automated sedation with propofol. Also known as CAPS (computerassisted personalized sedation), the machine monitors ECG, SpO2, etCO2 and
patient responsiveness to auditory commands while slowly titrating propofol in
small increments.
Sedasys® may decrease the rate of, or even stop, the propofol infusion but it
cannot increase the rate or provide bolus doses of propofol. As such, it is more
complex than the open loop Diprifusor® system but not a true closed loop system
that titrates drug against effect to achieve a hypnotic endpoint.
Sedasys® has received a CE mark in Europe for routine colonoscopy and
screening of the upper GIT, and Health Canada has also approved the device for
routine colonoscopies where conscious sedation is needed (not deep sedation or
general anaesthesia).(36)
FINALLY: THE SURFING ANALOGY
The central advantage of TCI is best described by a surfing analogy(figure 8).(17)
The pharmacodynamic approach relies on the measurement of effect to guide
drug administration whereas the pharmacokinetic approach relies on knowledge
of a drug disposition to deliver the drug to a required target concentration. The
pharmaceutic approach makes use of choice of an appropriate agent that reduces
the importance of exact knowledge of drug effect and delivery.
In the context of this surfing analogy, TCI can be viewed as a tool to explore the
wave while riding it. With a manual infusion pump, the “wave” that the anaesthetist
“sees” is not the concentration-effect curve but an infusion rate-effect curve.
However, this wave constantly changes. The relationship between the infusion
rate and what is happening in the patient changes every second.
Thus, the” wave” the anaesthetist is trying to surf constantly changes shape. Any
need to suddenly change depth of anaesthesia changes the shape of the wave or
even obliterates it. Therefore it becomes very difficult to characterize the wave,
other than perhaps recognizing that “this patient needs more or less drug than
average”.
With TCI, the ”wave” is the concentration-response relationship. Even though this
is based upon a predicted concentration the critical point is that the wave does not
Page 23 of 29
change shape during the ride to shore. A targeted effect site concentration should
yield a given effect irrespective of the time elapsed. (17)
Figure 8 : Surfing analogy(17)
Anesthesiology. 2003;99(5):1037–44
The analogy represents a graphical description of how anaesthetist use combined
approaches to administer anaesthetics to provide sufficient anaesthetic depth
while enabling rapid recovery. Anaesthetists target the upper portion of the “steep”
part of the dose –response curve where small decreases in concentration are
associated with large decrements in drug effect at the end of the anaesthetic; this
can be viewed as a surfer riding the crest of a wave.
CONCLUSION
Target controlled anaesthesia takes much of the uncertainty out of application of
pharmacokinetics and pharmacodynamic principles. Complex mathematical
equations are incorporated into models and patient variables are taken into
consideration. These devices simplify intravenous drug administration by relieving
the clinician of tedious calculations and by eliminating calculation errors. (2) With
the incorporation of effect site monitoring, we will be able to put more pieces in the
puzzle and complete the picture. TCI is most certainly not a toy but a tool in
evolution.
Page 24 of 29
COMMENTARY
Gavin Jones
It has already been highlighted that most of the studies concerning TCI & the
validation of models have been performed on small numbers of patients which fit
into level 2b of the Evidence Pyramid ie:
 Marsh model derived from 18 pts
 Schneider 24 volunteers
 Kataria 53 children
 Marsh paediatric model 10 children
 Paedfuser 29 children.
The nature of PK studies is that they do not need that many subjects because
what is important is the derivation of PK parameters on individual subjects, which
are then summarised as means etc. These are then used in constructing the
computer algorithms by way of intercompartmental rate transfer constants. The
algorithms should then be validated using real-time plasma concentrations in the
clinical setting.
LEVEL 2b EVIDENCE
From: Medical Research Library of Brooklyn
http://servers.medlib.hscbklyn.edu/ebmdos/2100.htm
Page 25 of 29
33 references have been used to compile this booklet. These references have
been graded as follows:
No.
Systematic Reviews 7
RCDBTs
Cohort Studies
9
Case Control
Studies
1
Case Series
Case Reports
Editorials &
Opinions
16
Animal Research
In Vitro Research
References
2, 5, 6, 8, 11, 29, 32
7, 13, 14, 15, 18, 19, 22, 23, 25
26
1, 3, 4, 9, 10, 12, 16, 17, 20, 21, 24, 27, 28, 30, 31,
33
There are numerous cohort studies on TCI but no large randomised controlled
trials (RCT's) and clinical outcome studies looking at the role of TCI devices. One
systematic review comparing TCI to MCI (manually-controlled infusion) was
published in the Cochrane library in 2012 and was based on 20 “poor quality”
trials, which included 1759 patients.
The objective was to assess whether TCI of propofol is as effective as MCI of
propofol in terms of quality of anaesthesia or sedation, adverse events and
propofol drug cost. TCI was associated with higher total doses of propofol but
there was no difference in quality of anaesthesia and sedation as well as adverse
events.
The authors concluded that this systematic review did not provide sufficient
evidence to make firm recommendations about the use of TCI versus MCI in
clinical anaesthetic practice. (31)
This reaffirms our conclusion that there is continuing uncertainty as to the value of
TCI devices. There are clearly advantages to their use that don’t add up to
outcome benefits at present. However, it is important to remember that the
absence of evidence is not the same as evidence of absence.
Page 26 of 29
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