TCI practical Tips for use 5ed June 2023.pdf

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TCI - Target Controlled Infusion
Practical tips for use
5th edition, June 2023
Antonio Farnia
Annapaola Dotto

TCI - Target Controlled Infusion
Practical tips for use
20 years of use and experience in the Ca' Foncello regional hospital in Treviso, Veneto,
Italy.
Free thoughts on modern clinical pharmacology and advice on a safe and simple
modality of the TCI technique.
5th edition
June 2023
Each portion of this document can be used in all its parts without Copyright and shared freely
with anyone interested in its content.

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Index
Presentation........................................................................................................................................ 1
The advantages of TCI.................................................................................................................... 3
Introduction and definitions........................................................................................................ 4
Pharmacokinetic models............................................................................................................... 6
Accuracy of a model.......................................................................................................... 7
Propofol…………………………………………………………………….......................................... 8
Propofol Eleveld model.................................................................................................... 10
Opioids.................................................................................................................................... 12
Dexmedetomidine, midazolam and ketamine......................................................... 15
Practical way of functioning.......................................................................................................... 17
TIVA…………………................................................................................................................... 17
TCI anesthesia…………………................................................................................................ 18
Dosage Recommendations............................................................................................................ 24
Sedation................................................................................................................................... 24
General anesthesia............................................................................................................... 27
How to conduct anesthesia in TCI.................................................................................. 27
Anesthesia with propofol, sufentanil e remifentanil……......................................... 35
General anesthesia Treviso method version 2022.................................................................. 36
Requirements for Modern TCI Pumps and Systems 2023................................................... 38
Final Thoughts ..................................................................................................................................... 39
Simplified scheme .............................................................................................................................. 42

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Presentation
The production of this short manual is the result of the experience gained in more than twenty
years of use of TIVA/TCI, as well as during the theoretical-practical courses organized to
disseminate the skills necessary to use it. The main purpose is to provide simple advice derived
from the daily use of the method, made up of countless adjustments drawn from practical
experience and from the continuous revision of the literature.
The pharmacological aspects explained here are extreme simplifications of very complex
concepts: we will not deal with absolute scientific truths, mathematical or engineering
certainties, because they are beyond the scope of these pages. We realized that the literature
is currently missing precisely the information that would be most useful to an anesthesiologist
who wants to start using TCI.
The first question that the anesthesiologist asks is: what concentration do I use?
We have repeatedly seen recommendations to start with a predefined target: 4 μg/ml of
propofol and 4 ng/ml of remifentanil. In fact, some pumps are programmed to start the
infusion from a preset fixed concentration, but this exposes you to great risks of overdose
and can only be good in a small group of young and healthy subjects. For all the other
categories of patients - elderly, frail or at anthropometric extremes - who are also the most
frequent in our work, this method is not good.
So, we do not support this practice, but rather strongly advise against it.
You absolutely must not approach TCI by learning to set a priori a high target concentration
just to get a quick fall asleep and without thinking about all the consequences that this can
entail.
If we do not value the clinical pharmacology underlying the TCI modality, we might as well
continue to administer a bolus of 2-2.5 mg/kg of propofol and then set a pump to ml/hour
as it was done twenty years ago. We believe instead that using incremental steps and taking
the time necessary to do a good job for our patient, both at induction and upon awakening,
is one of the most important aspects of the anesthesiologist's activity. In the dynamics of an
operating room these are times to be considered non-compressible and certainly not so
consistent as to justify a superficial and hasty attitude.
The answer to the diverse patient population we encounter in our clinical practice cannot be
a one-size-fits-all magic number. We cannot know in advance the patient, his or her response
to drugs, his or her comorbidities and the conditions in which he or she has to face the surgical
operation. Choosing this strategy means giving up all the advantages of an extremely modern
mode of administration of anesthesia that respects pharmacology.

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Almost all patients fall asleep with less medication than we are used to administering; some,
few, with a larger quantity. If, for example, we use the Schnider model for propofol and
proceed in small increases in concentration and wait a sufficient time of 2-4-5 minutes, we
find that the total dose of propofol administered is often about 1 mg/kg of weight; therefore,
much lower than the canonical 2 mg/kg, with undeniable advantages in terms of
hemodynamic stability. It is as if for each patient we built an individualized pharmacodynamic
curve that allows us to customize our general anesthesia. If, on the other hand, we start with
a predefined concentration, we give up this advantageous possibility.
Other frequently asked questions are: which model should I choose?, plasma or effect mode?,
how do I start?, how do I set anthropometric data?, are there any tricks I should know?, which
combination of drugs is most suitable?, how much drug will the pump administer?, the model
I have chosen is safe for the patient?, once induced, how do I maintain anesthesia?, when
should I stop the infusion?.
These are just some of the questions we have tried to answer in a simple and understandable
way for everyone.
Happy reading and excellent work!

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"All models are wrong, but some are useful".
George Box – 1979
The advantages of TCI
When you try to summarize and clarify a complex biological phenomenon with a model, what
you get is in most cases a rough simplification of reality. This for example happened in the
context of the study of the coagulation cascade and the interrelation of its factors but,
however inaccurate those models were, they performed their didactic purpose very well.
We will make some pharmacological and operating concepts of TCI pumps usable so that you
can use this anesthesiological modality with serenity in daily practice.
Experts of this technique, in Italy and around the world, have often failed to effectively convey
this knowledge, because they have gone too far in analyzing the underlying mathematical
aspects. Aspects that are not necessary for the anesthesiologist to be able to do a good
anesthesia.
Before each course we ask ourselves what is the keystone to excite the learners, such as to
entice them to try this method: how to express the "essence" of TCI, that is, the characteristics
that make it an extremely interesting mode of administration of anesthesia?
Well, we will condense these characteristics into three fundamental aspects:
1. Simplicity: TCI allows you to administer anesthesia in a very simple way, as happens
for inhalation anesthesia in which you set a certain percentage of vapor exhalation or
MAC. Choose a Target value (e.g. 3.2 μg/ml at the effect site) and the pump software
takes care of obtaining and maintaining this concentration. So, to begin, it is sufficient
to know which concentrations are adequate to obtain a certain clinical effect. TIVA is
not as simple;
2. Quality of awakening: it is one of the most interesting aspects of intravenous
anesthesia. The patient's awakening is quiet, cooperative, and lucid and this condition
- clear headed - is achieved earlier and better with intravenous drugs, administered at
the correct doses and concentrations, than can be obtained with even faster kinetic
inhalation anesthetics such as desflurane;

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3. Stability of the anesthetic plan: when the anesthesiologist sets a target
concentration, the TCI system takes care of administering the right dose of drug to
reach the set target as quickly as possible and subsequently varies the infusion rate of
the pump over time, considering clearance and distribution, to maintain the desired
target constant until the anesthesiologist decides to change it. Administering a bolus
to increase concentration, stopping the infusion when we decide to reduce it and
varying the infusion rate during maintenance are peculiar characteristics of a TCI
apparatus. Only with such a fast and precise system is it possible to have precise control
of anesthesia. A stable anesthetic plan is an indispensable requirement, but often
underestimated, of a quality anesthesia because a careful, precise, accurate conduction
means that we have administered the "right dose of the anesthetic mixture at every
moment of the operative act".
In this way we can finely correspond to every small variation of surgical stress,
hemodynamics. This can only correlate with a lower risk of organ failure and a better
outcome for the patient when compared with a wave and shaky management (alpine
anesthesia with peaks and valleys), always in the late pursuit of an adequate anesthetic
level.
Many of the anesthesiologists to whom we tried to pass on this technique learned by reading
these simple tips and bringing them to the operating room the first few times they used TCI.
These are suggestions derived from our experience and sensitivity, but as we all know, the
way of doing anesthesia is extremely varied and must be appropriately declined at the service
of the patient in front of us.
Introduction and definitions
Target Controlled Infusion (TCI) is an intravenous mode of drug delivery, which uses
pharmacokinetic models developed on a sample population and integrated into dedicated
infusion systems.
TCI means that the administration of the drug is controlled by a target, i.e. a concentration
level set by the anesthesiologist. The computer system will take care, through the pump, to
quickly reach the target and keep it stable, adjusting the infusion rate and avoiding both
overdose and underdose of the drug. No calculation is required from the anesthesiologist.
Unlike Total Intra Venous Anesthesia (TIVA), TCI allows fine control of drug administration
and rapid change in target concentration, making the anesthesia plan extremely easy to
handle. An implicit concept in TCI mode, in fact, is that the target concentration can be

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changed whenever the anesthesiologist deems it necessary, to follow in real time the various
phases of surgery, correcting hypnosis and analgesia in a timely manner.
The accurate modulation of analgo-sedation makes TCI an incomparable tool when we find
ourselves having to sedate very complex patients outside the operating room (NORA – Non
Operating Room Anesthesia), with the need to offer adequate anesthesiological comfort to
the patient, avoiding accidental overdoses and episodes of respiratory depression.
TCI abandoned the TIVA mode of administration at mg/kg body weight for bolus and
mg/kg/h or μg/kg/min for continuous infusion, since current or ideal body weight or lean
body mass were insufficient indications for proper drug dosage. When we administer any
drug to a patient, this, by distributing itself in the plasma volume, generates a concentration
and it is this concentration that determines after some latency the expected
pharmacodynamic effects. To put it another way: when I administer a drug, what I want is to
quickly obtain a well-defined effect and for this to happen the drug must reach a given
concentration at the level of the receptor on which it acts. Given the nature of the drugs we
commonly use, we would also like to administer the exact amount, even more so in the case
of a continuous infusion, because we would like our patient to enjoy a pleasant anesthesia
and wake up as soon as the surgery is over.
And whether there are patients who, despite having the same body weight, have extremely
different age, muscle mass, state of health, circulation conditions and metabolism. So, it is
quite simplistic to quantify the appropriate drug dose for each patient only based on weight.
Weight that remains an important covariate to calculate the dose necessary to match the
target and determine the concentration reached as the infusion continues.
The target is the concentration of the drug referred to a certain compartment of the body,
which can be:
a. plasma is therefore the concentration I want the drug to reach in the patient’s plasma
(plasma target);
b. The effect site then the concentration referred to the site where the drug exerts its
pharmacodynamic action or binds to its receptor (target to the effect).
The plasma target - typical of the Marsh model for the propofol of Diprifusor - is now little
used and will be abandoned, as plasma is only the means of transport of pharmacological
molecules, which sooner or later balances with the effect site, which instead represents our
true pharmacological goal.
The methods of administration of plasma TCI and effect differ from each other.

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The administration with plasma target requires, when we set a target, that the software
imposes for a short time a high speed to the pump, such as to quickly reach the desired
target; as the target approaches, the pump slows down its infusion rate and continues at
variable speed to keep the target constant. Plasma TCI never administers a bolus and never
exceeds the imposed plasma target.
The mode with target to the effect instead always administers a bolus when we set a target
greater than the present one. The system will calculate a plasma bolus that will allow to reach
as quickly as possible the balance between plasma and effect site and will always consider
the target concentration to the effect to be achieved. This modality is very similar to that used
to induce children with sevoflurane: an inhaled concentration of sevoflurane is set at 8% for
a few breaths, so that there is a rapid spread of halogenate until the child is induced;
subsequently the concentration is reduced to 2-3% (1.5-2 MAC) which is the value suitable
for maintaining anesthesia.
In effect mode, the system instructs the pump to administer a bolus to create a plasma peak,
then the pump stops. Overshooting results in a rapid passage of molecules from the plasma
to the effect site. After stopping the pump resumes infusing and variable speed.
Therefore, effect TCI works by reaching a desired concentration at the receptor level more
quickly than the plasma mode.
Pharmacokinetic modelling
A pharmacokinetic model is the description of changes over time in the concentration of
a drug, injected into the venous system. Ideally it should be able to describe the dynamic
evolution of this concentration in every tissue of the body, but unfortunately all attempts to
measure the concentration of a drug in the various organs have never given satisfactory
results. The variations in concentration detected with non-standardized arterial or venous
samples, performed at times varying from the administration of the drug, are not always
reproducible due to the dilution times of the molecule and the cardiac revolution. This is
especially true of the behavior of the drug immediately after intravenous administration –
front-end kinetics – until a steady state is slowly reached. Even more complex is to define
what is the real concentration of the drug in the effect site or biophase: philosophical
concept used to define the latency between plasma peak and clinical effect detected.
Therefore, when we refer to concentrations at the effect site, we will always mean plausible,
calculated, and unmeasured theoretical concentrations.
The construction of a model is obtained through seriated blood samples (arterial or venous),
performed after the administration of the bolus drug, followed by continuous infusion, and
evaluating the concentrations obtained at predefined times. The samples are usually derived

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from a small population of healthy volunteers with contained anthropometric data and the
results of the measurements are then introduced into a statistical simulation program called
NONMEM (NON-linear Mixed Effects Modelling), which analyzes them and transforms this
small group into a larger population, where it expands the few available data by deriving a
population analysis.
This allows to draw the curve of the concentration of the drug over time. The resulting
compartmental drug model consists of distribution volumes (V1 central compartment or
plasma, V2 rapid compartment or highly perfused organs, and V3 slow compartment or
poorly perfused tissues), transfer constants between different compartments and terminal
elimination clearance. The dimension and compartments do not correspond to real
anatomical volumes but originates from the physical and physiological characteristics of the
drug analyzed and the same applies to the transfer constants. The tricompartmental model
is the most appropriate to describe pharmacokinetics in primates and humans.
Over the years, various pharmacokinetic models have been produced, with the aim of
describing as accurately as possible the behavior of the drugs we use and guiding their
administration during anesthesia. For propofol, for example, there are many, built for peculiar
populations and with different performances. Many of these have never been introduced into
commercial pumps and, apart from the historical and experimental value, they have never
come to extensive use. Each model is named after the first author of the publication who
describes it, for example:
• propofol: Marsh, White & Kenny, Schnider, Servin, Marsh II, Kenny, Short, Shüttler,
Jeleazcov, Vuyk, Li Ih, Balley, Cotzee, Doufas, Billard;
• sufentanil: Gepts, Bovill, Greeley;
• remifentanil: Westmoreland, Dershwitz, Egan, Glass, Pitsu, Sam, Kim, Abbiati Minto.
To be approved and marketed, however, they must demonstrate precise performance
characteristics, i.e., they must be reliable and reproducible.
Accuracy of a PK/PD model and TCI system
To determine the performance of a TCI system and a PK/PD model, it is necessary to compare
the measured plasma concentrations with those predicted by the model. A model is reliable
if the real plasma concentrations are close enough to the theoretical concentrations indicated
by the machine.
Briefly, the criteria currently used for this purpose are:
 Median Performance Error (MDPE): Measurement of bias or over-infusion. If MDPE
is zero, it means that the model does not make any mistakes. When MDPE is greater

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than zero, an underestimation of the actual concentration is observed, so the
measured concentration will be higher than the theoretical one we read on the pump,
and we risk administering more drug than we think. Conversely, if MDPE is less than
zero, we are administering less medication than the model predicts;
 Median Absolute Performance Error (MDAPE): indicates inaccuracy or inaccuracy
in pump prediction;
 Wobble: or oscillation, is the measure of the variability of intra-individual errors;
 Divergence: indicates the rate of change in absolute performance error over time.
When it is negative it means that the bias remains unchanged over the hours, so it
does not tend to increase further. It is a measure of divergence over time in terms of
the size and magnitude of errors.
For TCI pumps an MDPE of 10-20% and an MDAPE of 20-40% is considered acceptable.
These are universal criteria in this area and must also be met by vaporizers calibrated for
inhalation anesthesia. The poor performance of an anesthesia delivery system precludes its
placing on the market.
Models for propofol
TCI pumps have made available some pharmacological models for propofol – including
Marsh and Schnider – and for each of these we can decide whether to use them with plasma
or effect targets.
The Marsh plasma model (the first commercial model) was implemented in the original
Diprifusor® systems; therefore, it is more familiar to older TCI users and, although there is
now the possibility of administering it to the effect, it must be used in plasma, otherwise
the induction dose would be too high.
Marsh may be more satisfying in young patients in good condition because they allow faster
induction: it delivers a higher dose of propofol, which makes it resemble common TIVA
inductions performed with the 2 mg/kg manual bolus.
The model that my group has used daily for propofol over the past decade is the Schnider
effect mode. The choice of a single model for propofol, within the same service or hospital,
derives from safety recommendations, which consider the free choice between various
models an additional risk factor, in terms of incorrect programming and poor ability to use.
The Schnider model uses as covariates: age (absent in the Marsh), weight, lean mass (LBM)
and sex and has a central compartment (V1) of very small volume, which corresponds to a
calculation of the induction dose equally reduced. This involves the administration of a low
total dose of drug (about 1-1.5 mg/kg to get the patient to sleep), with a slow induction and

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respectful of hemodynamics, characteristics that make it the best model in elderly or
compromised patients. The delicacy of such a pattern reflects the significant reduction in
clearance of the drug from the blood, which correlates precisely with age.
On the other hand, it is disadvantageous in cases where rapid induction is required.
The Schnider model must always be used to the effect otherwise, with a plasma target, the
induction would become dramatically long. Having this model a small V1 and delivering a
relatively low amount of medication, without the initial bolus, would in no way be able to fill
the V1 and our patient would never fall asleep.
Another problem inherent in the Schnider model is that, using James' formula for calculating
lean body mass, it cannot be used in obese patients, to whom he would administer too small
a bolus, determining on the other hand a significant accumulation for prolonged infusions.
There are currently two validated models to guide the administration of propofol in obese
patients: the Cortinez-Sepulveda allometric model and the Eleveld allometric model.
Allometry is the study of biological processes in relation to the size of living beings - for
example it correlates the metabolic rate in basal conditions of a mammal with its body mass
- and uses Total Body Weight (TBW) as a descriptor of volumes and clearances. It seems that
allometric models are more performing in transposing pharmacokinetic/pharmacodynamic
processes and are increasingly used in modern PK/PD models.
Some TCI systems also have paediatric models for propofol, which until recently were only
found as plasma models, due to the relative difficulty in quantifying the time to peak effect
(TTPE) in the paediatric population. The condition of incomplete maturation of the central
nervous system typical of the child, in fact, makes it more difficult to monitor hypnosis with
the usual systems. Since some years, however, in certain commercial systems, the Kataria and
Paedfusor models have been available with effect modes.
A characteristic that pediatric models have in common is having a central volume almost
twice as large as that of adults – for example, the Paedfusor has a V1 of 9.2 L vs Schnider 4.27
L – which corresponds to the actual need for higher dosages to induce anesthesia in children.
Kataria model was born in 1999, designed for children aged 3 to 11 years, with a minimum
settable weight of 15 kg. The substantial covariate of this model is the weight and the
compartments that compose it grow linearly with it, while the transfer coefficients are fixed.
In using this model, it is better to expect a reduction in maintenance concentrations with
increasing age, otherwise it tends to administer little too much medication.
The Paedfusor model uses weight and age as a covariate, it can be used in children from 1
to 12 years with weight above 5 kg. It is the most common model among pediatric users,
due to the wider age range and the possibility of use in young children, as well as for the best

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performance (Paedfusor MDPE % 10.4 and MDAPE % 34.1 vs Kataria MDPE % 31.3 and
MDAPE % 34.1).
The Eleveld model for propofol
A new allometric model for propofol is currently available for general purpose - developed
by Prof. Eleveld, Groningen, The Netherlands. The model was built drawing from 30
pharmacokinetic studies and 5 pharmacodynamic studies (with data obtained from the Open
TCI Initiative which provides for the sharing of many studies and authors), therefore includes
a population of 1033 patients aged between 0.5 (27 weeks) and 88 years and a weight range
from 0.68 to 160 kg. The covariates considered are age, weight, height and sex. The same
group also developed an Eleveld+opioid model that considers synergism with consensually
infused opioids and at the same set concentration administers less propofol. The
pharmacodynamic interaction with the opioid allows a reduction in the concentrations of
propofol necessary to achieve a certain clinical objective (e.g. a BIS target of 50). The
performance of these extended-use models was evaluated on five patient populations:
infants, children, adults, the elderly, and individuals with high BMI. The model showed good
pharmacokinetic performance, better than those of previous models (MDPE of -1.4% and an
MDAPE of 21.5%) and equivalent to the performance of Paedfusor in children. The less
satisfactory performances have been observed in large obese patients, but they are still
similar to those of the Cortinez model which is still the reference algorithm for this category.
The greatest advantage of the Eleveld model, in addition to the improvement in performance,
is to make unnecessary the choice of a model appropriate to the type of patient we are facing,
they will be the anthropometric data, introduced by the anesthesiologist, to determine the
working mode of the pump and the correct doses to achieve the desired targets.
One model that fits everyone.
Treviso experience with the Eleveld model
Since October 2019, the Eleveld and Eleveld+opioid models have been introduced in the
Arcomed pumps, in use at the Anesthesia and Reanimation Unit of the Ca' Foncello hospital
in Treviso.
These new models have met with wide acceptance among anesthesiologists and we all
currently use Eleveld+opioid for the induction and maintenance of anesthesia in all surgeries
(general surgery, gynecology, ENT, maxillofacial, urology, thoracic surgery, orthopedics,
plastic and breast surgery, robotic surgery, neurosurgery, pediatric surgery and cardiac
surgery) and for procedures in NORA (endoscopy digestive, interventional radiology,
magnetic resonance sedation, rigid and flexible endoscopy of the airways).

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The goal of the Groningen group was to create a unique model for propofol with high
predictive power, able to adapt to a wide range of patients and be used in multiple
intraoperative scenarios.
The immediacy of the interface and the adaptation of the model to the patient have proved
to be eschatological: in our clinical activity the Eleveld+opioid has substantially replaced the
Schnider and is also used instead of the Paedfusor and the Cortinez, with great satisfaction
on the part of the operators.
As had previously happened with the Schnider, it was decided to use a single model that is
the same for everyone, to standardize the method, reduce the risks and increase the skills of
individual operators.
Mistakenly, some think that the ideal model is the one created on the sample population
most adherent to the patient and for this reason in the past models of all kinds have been
developed (for example, we have tried to build models suitable for various populations based
on ethnicity or some phenotypic characteristics), while instead a universal model corrects
pharmacokinetic errors derived from the analysis of a restricted population, ensuring better
results.
What then makes the difference in daily practice is the habit of exploiting the potential of the
model by adapting it to the patient's critical issues, precisely because they have experience
of it. Many experienced users of TCI technique say that the best anesthesia is expressed by
pulling the target on the patient and then modulating induction and maintenance on
monitoring, clinical and surgical timing.
We have learned to use Eleveld+opioid in young people, knowing that if we conduct low
opioid anesthesia, we will have to maintain moderately higher target concentrations of
propofol than we were used to doing with previous models, because this model considers
synergism and greatly reduces the infusion of propofol as the hours go by. With this model
the decrement time can be more usefully set to a concentration of 1.2 - 1.4 μg/ml - much
higher than the Schnider model, - especially if we associate remifentanil that in the
intraoperative leads us to a saving of the hypnotic and has however an extremely short half-
life.
In the elderly, it is always advisable to increase the target concentration at induction in
progressive steps, avoiding large variations, to respect their fragility. Compared to the
Schnider model to which many of us were accustomed, in fact, the Eleveld proves to be more
generous in the induction phase and setting a high target can be dangerous, as well as
unnecessary. Precisely for this reason it is of great satisfaction in the young patient, because
we can put him to sleep more quickly than we did with the previous model.

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For those delicate patients, who woke up with Schnider with concentrations of 0.6–0.8 μg/ml,
with Eleveld+opioid it is generally sufficient as an awakening concentration of 1-1.2 μg/ml to
have a reliable indication.
Even in children the fall asleep is faster, because of the more conspicuous bolus, but the
feeling is that for prolonged infusions lower concentrations are sufficient than in Paedfusor.
We also abandoned the Cortinez model, which we used for the obese or in any case in cases
where the high BMI did not allow us to use the Schnider: the Eleveld+opioid allow us to work
with peace of mind, without the worry of an inconvenient accumulation.
We could summarize our positive experience by saying that, in a short time, this new model
has spread in a cascade from one anesthesiologist to another without us almost noticing,
precisely because it has simplified our daily practice.
Models for opioids
In clinical practice, opioids that can be administered in TCI and are currently used are
remifentanil and sufentanil.
Sufentanil
Sufentanil is an opioid certainly underestimated by anesthesiologists despite being the drug
of this family with the highest therapeutic index: LD50/DE50 26,716, compared to fentanyl
277 and morphine 71, therefore the safest to use. It is very powerful, ten times more than
fentanyl and a thousand times more than morphine, so it ensures excellent analgesia, but at
the same time it benefits from a much lower incidence of respiratory depression.
The reasons for its scarce use lie in the habit, well rooted in us anesthesiologists, to use
fentanyl, which remains the most known and used opioid in the world, even if for its
characteristics PK/PD would be a drug to be handled carefully. Sufentanil, which has a cost
equal to or less than fentanyl, is like the latter an opioid with a medium half-life, but with a
much more advantageous kinetics, greater certainty in decrement and less accumulation. The
TTPE of sufentanil is 6-8 minutes, slightly slower than that of fentanyl (about 5 minutes), a
negligible difference regarding the induction and control of intraoperative variations. Given
this relative slowness in the plasma-biophase balance, it is possible in TCI to select from the
definitive target principle of 0.2-0.3 ng/ml - adequate concentration to cover the stimulus of
laryngoscopy particularly when combined with remifentanil - without having to climb steps
and without incurring chest stiffness. Its high analgesic power allows an extremely satisfactory
control of pain during major surgery, with relatively little hemodynamic impact, giving
anesthesia a stability not reachable with bolus fentanyl or with remifentanil alone. It also

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allows you to predict the time needed to recover an adequate respiratory drive at the end of
surgery, with known concentrations ranging from 0.12 to 0.18 ng/ml and make safe, quiet,
and delay-free extubation possible. There is no risk of accumulation if appropriate
intraoperative targets are used, administering for medium-duration surgery a total quantity
around 1 μg/kg.
It ensures adequate postoperative analgesia for at least one hour after the conclusion of
surgery. It is a handy and versatile drug, which expresses its potential also in the management
of postoperative analgesia with simple elastomer or even better with PCA pump. Thinking of
our patient from the point of view of tricompartmental pharmacokinetics, we can say that the
rate with which the sufentanil molecules are eliminated from the central compartment (V1)
will always be greater than the speed it takes the same molecules to redistribute from the
peripheral compartment V3 to the central one. Therefore, once the infusion of the drug has
been suspended - and the V2 fast-flow compartment balanced with the V1-, it cannot
"reaccumulate" at the level of the effect site or determine paradoxical plasma peaks, avoiding
the risk of an impairment of the waking state or depression of the respiratory drive.
The currently commercially available models for sufentanil are Gepts and Bovill. Neither of
these allows the use of sufentanil in the paediatric patient; Greeley’s PK model for babies
and children from Bovill was never introduced into commercial pumps. The Gepts model
can offer a good performance in a wide range of patients, large children, adults, obese and
the elderly, for this reason it has a wide diffusion and many admirers. This model does not
have covariates, so there is no change in the dose administered depending on the weight,
height, age, or sex of the subject. Despite being an outdated model (published in 1995) the
Gepts model works very well and is absolutely reliable: it is currently the most widely used
PK/PD model for sufentanil in the world.
The Bovill model (1984) present in some of the pumps on the market, has instead the weight
as covariate, but its performance is comparable to that of the Gepts, so in clinical practice the
choice between the two models is irrelevant. Bovill, compared with Gepts, in an adult patient
with the same anthropometric parameters and at the same set concentration of 0.3 ng/ml,
administers a slightly higher amount of drug both at induction and during maintenance at
thirty minutes, as after five hours of infusion.
Sufentanil is unfairly neglected by researchers, but we hope for the release of an allometric
model that provides us with a better ability to control the infusion, more information on the
time to decrement and that allows us to administer it to a wider range of population including
the newborn and pediatric patient.

14
Remifentanil
The Minto model is a very solid one, used all over the world for more than 20 years with
great satisfaction. It comes from the study of 65 healthy volunteers using EEG to assess the
opioid effect.
Its distinctive covariates are age, weight, lean body mass and sex. It is a model that works to
the effect with a TTPE of 1.2 minutes and allows – thanks to the unique characteristics of
remifentanil – a fine control of painful phases and intraoperative stress.
It demonstrated an acceptable performance, with an MDPE -15% and an MDAPE 20%.
However, it also has limitations: the impossibility of employment or in the pediatric
population under 16 years; poor performance in patients with high BMI because, like Schnider
model, it uses James' formula for the calculation of LBM.
Recently we have seen the commercialization in some TCI pumps of the Eleveld model for
remifentanil: allometric model with extended use that will allow its safe use also in the
pediatric population as well as in adults. This model considers pharmacokinetic and clearance
changes related to maturation of metabolic systems, making administration correct at all
ages. Distinctive elements are, in addition to the greater number of patients used (Eleveld
131 vs Minto 65), the wide age range from 5 months to 85 years.
From a purely practical point of view, in normal weight adults not much changes compared
to when we use Minto, except for a more careful maintenance infusion, with a certain saving
of drug and therefore perhaps lower risk of hyperalgesia. What are extremely interesting
concerns the fine calibration of the administration in the pediatric patient for which,
compared to the Minto that some of us sometimes used the same cheating on age, for the
same target concentration it works at an infusion rate that is about a third, thus substantially
reducing the risk of bradycardia.
Another allometric model for remifentanil is the Kim-Obara-Egan, built on 229 patients, with
the limit, however, of having been tested on a population similar to that of the Minto model,
i.e. patients between 20 and 85 years. The Kim-Obara-Egan model allows the safe use of
remifentanil even in large obese patients, with a weight of up to 215 kg.
Other opioids alfentanil, fentanyl, morphine
Regarding opioids such as fentanyl (Marsh II and Shafer models) and alfentanil (Maitre
model), there is virtually no use in the literature in TCI mode. Although both are available in
some commercial systems, the pharmacokinetics of these molecules are so inconvenient in
prolonged administrations, with very long decrement times, that there is no clinical use, if not
experimental. The fact remains that, if we were to administer them in continuous infusion, it
would be much better to use them in TCI mode than in TIVA: the TCI considering the

15
accumulation would progressively reduce the infusion rate and therefore the total dose
administered, maintaining the desired concentration stable.
For morphine there is the Sarton model that describes its pharmacokinetics, but to our
knowledge, this model is not available in any commercial pump and is applied for simulation
purposes only (on the other hand very didactic).
Other drugs: dexmedetomidine, midazolam and ketamine
Another potentially interesting drug for use in TCI is dexmedetomidine (Dyck and
Hannivoort-Colin models), endowed with sedative-analgesic qualities and inhibition of the
sympathetic system, which will probably see a more extensive intraoperative use when the
drug agency will license its use for this purpose. Very interesting is the introduction as an
adjuvant during general anesthesia, both in inhaled and intravenous, to minimize the risk of
delirium and postoperative cognitive impairment (Postoperative Delirium and Postoperative
Cognitive Dysfunction).
Now its use is limited to procedural sedation or during radiological examinations, especially
in pediatric patients, and in neurosurgery in awake craniotomy where it is necessary to have
an awake, collaborating, oriented patient with a fair anxiolysis and analgesia. During
procedural sedation and analgo-sedation in intensive care an appreciable feature is the
possibility of having a patient sleeping, but awakenable to the call. This is the fundamental
characteristic that distinguishes dexmedetomidine from all other hypnotics.
In addition, it has peculiar electroencephalographic characteristics, that is, it produces a sleep
that mimics the physiological one and is distinguished from anesthetic hypnosis by the
presence of sleep spindles: alpha wave trains of frequency between 9-15 Hz lasting 0.5-1.5
seconds typical of the NREM-2 phase of sleep, which alternate with slower delta waves.
A negative aspect to consider is that it expresses, in a first phase, an activity of stimulation of
the central α2 receptors which inevitably follows, after bolus, an increase in blood pressure
and heart rate. Then the alpha-lytic effect takes over with lowering of blood pressure and
bradycardia. These effects limit its use in some patients. Consider, however, that, as with all
drugs, desired and unwanted effects are dose dependent, so we will have to be the ones to
have control of the speed of administration and the total dose infused.
Another problem is its extremely slow kinetics (TTPE of at least 15 minutes after bolus), so it
takes a long time to reach the desired target concentration and is also redistributed and
metabolized very slowly, giving rise to a considerable accumulation.
The pharmacokinetic model of Dyck has important limitations as it uses the patient's height
as the only covariate, while weight and age have no influence. It only works in plasma mode

16
so, considering the PK characteristics of dexmedetomidine and the administration without
bolus, it is necessary to start sedation much earlier than we are used to doing with propofol
to have a patient adequately analgo-sedated at the right time. Despite these limitations, we
used it with satisfaction in TCI mode.
The recommended dilution is one ampoule of 200 μg in 50 ml, to have a final concentration
of 4 μg/ml. The concentrations useful for sedation, which allows a rapid response oriented
to verbal stimuli, are 0.15-0.25-0.35 ng/ml. What must always be paid attention to is the
total infused quantity and the decrement time - on the calculation of which, however, the
Dyck is poorly performing - because bradycardia phenomena can occur even at a distance,
and it can be risky to go to high concentrations with patients who are then discharged at the
end of the procedure.
Above 0.7 ng/ml you lose the ability to respond to the stimulus and the memory of the
events that occurred. However, these concentrations determine consistent and prolonged
sympatholytic effects, so that a benefit ratio for the patient is lost. Such high concentrations
should never be used when combining dexmedetomidine with general anaesthesia. A good
strategy for those who use Dyck in the operating room is start the infusion after intubation,
going up in progressive steps at low concentrations (0.1-0.25 ng/ml), and then suspend the
infusion well in advance of the end of the surgery.
Always remember that the decrement times and the corresponding recovery times are
extremely long and in this the information generated by the software, although not very
accurate, is extremely didactic.
For several months we have also had the Hannivoort-Colin model available: a
tricompartmental allometric model, which has weight as its only covariate and which can be
used in subjects aged between 16 and 99 years, with a maximum weight of 113 kg. For an
effect version, it was licensed for clinical use only in the plasma mode, to prevent bolus-
related hemodynamic adverse events. Therefore, when we vary the concentration upwards
the pump will increase the infusion rate, but never exceed 0.6 μg/kg/h.
It is a much more sophisticated model than Dyck, able to predict with extreme accuracy the
pharmacokinetics of dexmedetomidine and the plasma concentrations reached. The plasma-
biophase balancing time is about 40 minutes and the half-life after one hour of infusion is at
least 90 minutes. Precisely this improvement in the algorithm guarantees a more prudent
infusion and, with the same target, progressively reduces the infusion rate because it
considers the important accumulation of this drug, something that the Dyck model is not
able to do.
The only precaution to have with Hannivoort is to avoid going too high with the target in
high weight patients, because using weight as a covariate tends to be generous in the
induction phases, with the risk of incurring hypertensive peaks or excessive administration.

17
The pharmacokinetics of midazolam are described by the Greenblatt and Zomorodi
models.
The recommended concentrations to obtain a condition of sedation and progressively
deepen it up to a real deep hypnosis are 50-100-200 ng/ml. Extremely long decrement times
of the order of many hours should be expected, even after relatively short infusions.
Also, for racemic ketamine there is a marketed model that takes the name of Domino. It is
an effect model, which predicts an extremely rapid pharmacodynamic peak time, of the order
of 1 minute.
The indicated dilution is 10 mg/ml and targets of 0.1-0.2 μg/ml are recommended as
concentrations for analgo-sedation (which rapidly administer doses of about 5-10 mg), then
rising up to 0.4-0.6-0.8-1 μg/ml to obtain analgesia and dissociative hypnosis. The decrement
time of ketamine is very rapid, moreover, considering that in the context of multimodal
anesthesia ketamine is used at low doses, to essentially exploit its anti-NMDA effect and
counteract remifentanil hyperalgesia, targets of the order of 0.2-0.4 μg/ml are sufficient.
There is also the Clements model, used exclusively for simulation.
Practical way of functioning of TCI systems
TCI systems use pumps and the same intravenous drugs (propofol, remifentanil and
sufentanil) as TIVA, but they work very differently.
TIVA
For propofol, a BET-type infusion schedule (Bolus, Elimination, Transfer) is used, involving
an initial bolus of 1-1.5 mg/kg body weight, followed immediately by the start of a continuous
infusion at 10 mg/kg/hour for 10 minutes, then reduced to 8 mg/kg/hour for another 10
minutes and then lowered to 6 mg/kg/hour until the end of surgery. It is possible to descend
to lower speeds based on the indications of hypnosis monitoring, so it is possible to reduce
the dosages to 5-4 mg/kg/hour under longer anesthesia.
The objective of BET was to achieve and maintain a plasma concentration of approximately 3
μg/ml of propofol and serial dosages of propofol in patients' plasma demonstrated that this
objective was skillfully achieved and maintained.
As far as remifentanil is concerned, the TIVA method of administration does not include
boluses, because incorrect dosage indications in the early stages of large-scale use
(recommended initial boluses of 0.5-1 μg/kg) have led to frequent episodes of chest stiffness

18
precisely because of the very rapid balance between plasma and biophase. For this reason, in
clinical practice, bolus is generally never administered in TIVA, even when the patient is
curarized and no stiffness should be feared, and remifentanil infusion is commonly - and
erroneously - initiated after intubation, at rates between 0.05 and 0.5 μg/kg/min depending
on the extent of the surgical stimulus.
Remifentanil, despite being a drug with a very rapid kinetics, is not able to arrive in time to
the pharmacodynamic effect if administered in continuous infusion: if we demand variations
in concentration with modifications of the infusion rate only. Then also for remifentanil the
times will be very long, of the order of about ten minutes. To have a rapid increase in
analgesia, such as intubation protection or surgical incision protection, remifentanil MUST be
administered as a bolus, only then the pharmacodynamic peak times correspond to about 1
minute.
With remifentanil diluted as usual to 50 μg/ml, pump administration of small boluses of 10-
20-30 μg during induction, accompanied by careful ventilatory assistance of the patient, does
not pose any risk of rigidity. The most frequently used infusion rates are 0.08-0.1–0.2–0.3
μg/kg/min. In clinical practice, higher maintenance dosages should be abandoned given the
high risk of opioid hyperalgesia.
The presumption, common in TIVA, to evade the algic stimulus of laryngoscopy and
intubation with high doses of fentanyl (200-300 μg) is a practice that should be reviewed. It
being understood that if administered in time, fentanyl offers acceptable coverage, even if
not complete as with remifentanil, it is also true that once the stimulus of laryngoscopy is
finished, there is still a useless analgesic coverage. In fact, having a high opioid activity while
the field is being prepared and waiting for the surgical stimulus of the incision, is certainly
not useful for the patient, especially if compromised, as it can lead to hypotension and
bradycardia.
TCI anesthesia
TCI systems work differently.
The pumps on the market have chosen different starting strategies with immediate switching
on of the type of drug and the model for some, while in others anthropometric data or
rather the choice between TIVA or TCI mode. In some pump models, an initial concentration
of 2-4 μg/ml for propofol and 2-4 ng/ml for remifentanil is mistakenly suggested by default,
while, in our opinion, the initial concentration once the pump starts should be 0.
Zero is a valid target for TCI and zero will always be the starting target and the target end of
all my anesthesia.

19
The anthropometric data of the patient are set which, in relation to the chosen model, can
work as covariates and therefore influence the dosages and infusion rates. The pump software
controls the administration of drugs based on a compartmental pharmacological model.
This model provides a central compartment (V1) that we could roughly identify with plasma,
which is in equilibrium through round-trip transfer constants with a second compartment
(V2) consisting of fast-flowing tissues such as heart, brain, lungs, liver, muscles, kidneys, and
with a third slow-flow compartment (V3) represented by poorly vascularized body tissues and
adipose tissue.
What interests us is that when we administer an intravenous drug to a patient, it will promptly
distribute in the plasma (V1) and from here, depending on the transfer constants, it will diffuse
into the fast-flow compartment (V2) with a certain speed and more slowly reach the low-flow
tissues (V3). At the end of the administration, as the drug spreads from the central
compartment to the periphery and therefore its plasma concentration is reduced, part of the
molecules that are in the peripheral compartments, will tend to return to the plasma and from
here they will then be eliminated. This description is for didactic reasons only because the
dimensions of the effect compartment are negligible and do not participate in the
mathematical calculation and do not return to the plasma.
The tricompartmental model can be represented graphically with the Hydraulic Model,
consisting of three cylindrical tanks of different sizes representing the various compartments
(V1, V2, V3), connected to each other by pipes that have a diameter proportional to the flow
speed (transfer constants) between one tank and another. At the bottom of the central
cylinder (V1) there is an exhaust pipe that connects it with the outside (V0) and which
represents the elimination from the central compartment or clearance. So, imagine opening
a tap to fill the main tank with water: V1 gradually fills up and the level of water contained
inside it rises. Some of that liquid flows in the direction of V2 via a discretely sized pipe and
some water flows through a much thinner duct to V3, while another dimension is eliminated
from the drain hole at the bottom of the first tank. The water will continue to move from V1
to the peripheral tanks until equilibrium is reached, i.e. the height of the water will be the
same in the three tanks and the amount of water that is eliminated is equivalent to that which
is introduced into the system from the open tap: steady state has been reached). At this point,
if I close the tap, the water level contained in V1 will begin to fall being eliminated from the
drainpipe; Therefore, the direction of the flow will be reversed, and the water will start flowing
from the peripheral compartments to reach the central one. The water will return from V3
with a lower speed than that contained in V2, as the connecting pipe is very small, so V3 will
be the compartment that will empty more slowly.
The dimensions of the various compartments, connecting pipes and exhaust pipe vary
according to the chemical-physical characteristics of the pharmacological molecule

20
administered. So, a very lipophilic molecule will have a large V3 where it will tend to
accumulate and will be eliminated slowly as the return pipe to V1 will be of reduced diameter.
A fourth compartment (Ve) has been added to the tricompartmental system, which is the
effect compartment or biophase, functionally assimilable, for anesthesia drugs, to the
receptor located in the central nervous system and above all to the pharmacodynamic result
of the presence of the drug on the receptor. This compartment (Ve) lies inside the central
compartment (V1), being fed from it. When we enter a drug in the central compartment, it
will inevitably reach the effect compartment, with a delay (latency) typical of the drug itself.
When the molecule reaches the Ve, its pharmacological action is carried out and we can
observe its clinical effect on our patient. With the introduction of Ve, the time gap between
the pharmacokinetic distribution of the drug in the various tissues of the body (compartments
V1, V2 and V3) and pharmacodynamic effect has been bridged. The effect compartment is in
constant communication and balance with the central compartment so that the induction,
the filling of the V1, also fills the Ve, with the latency characteristic of the molecule.
At the end of the surgery, when the target concentration is brought to zero and the pump
stops, the fall of the concentration in the effect compartment follows that of V1, which is
determined in part by the clearance of the molecule and in part by the redistribution of the
drug between the various peripheral compartments. Paradoxically for some very fat-soluble
drugs, such as sufentanil and propofol, the total amount of the drug present in the body
could still be very high, but the share present in the V3 compartment and slowly reintroduced
into the V1 through the communication channels, does not affect the descent of
concentration in the central compartment, which then determines the decrement in the effect
compartment and the awakening of the patient. This is because, for propofol and sufentanil,
the size of the communication channel between V3 and V1 has a diameter smaller than the
drug elimination duct.
As a result, our patients wake up because drugs are redistributed and not because they are
eliminated, with the obvious exception of remifentanil. For this reason, the elimination half-
life has no clinical significance and cannot give any information on recovery and awakening
times. What matters instead is the context sensitive half time which, considering the
duration of the infusion itself, defines the time that will take the concentration of the drug at
the effect site to reduce by half. The context sensitive half time is determined by the typical
clearance of the drug, the duration of the infusion and the return of molecules from the
peripheral compartments, which slow down the fall in the concentration in the plasma and
consequently in the effect site.
The context represents the duration of the infusion. Commonly, in fact, the amount of drug
administered cannot be completely and quickly eliminated at the interruption of the infusion

21
and the time necessary for this to happen is dependent on the context because: the longer
the duration of administration, the greater the accumulation of the drug. This is except for
remifentanil, as the formidable clearance capacity of the enzyme system – non-specific
esterases present in all tissues of the body – which metabolizes the molecule, makes its
pharmacokinetic profile unique. The context sensitive half time and the resulting decrement
time are better parameters to give indications on important clinical objectives such as: the
potential accumulation of the drug and the hypothetical awakening time or the adequacy of
the analgesic effect at the end of the operation.
The decrement time is the time it takes to have a decrement in concentration at the effect
site not by 50%, which commonly cannot lead to useful clinical changes, but by 70-80-90%.
All TCI systems allow to set a hypothetical decrement time, or rather a concentration in
relation to which the software calculates the time necessary for the latter to be reached once
the infusion is suspended. The concentration of awakening varies according to the clinical
condition of the patient, age, comorbidities, and the response that we have shown during the
induction and conduction of anesthesia. We will be the ones who, knowing the molecule in
use, model and having evaluated the patient's behavior, will choose the desired decrement
time amount.
How a TCI system works
When at the beginning of anesthesia, or sedation, we set a concentration to the effect (for
example 0.8 μg/ml) of propofol, the computer - based on the anthropometric data of the
patient introduced and the selected pharmacokinetic model - indicates to the pump to
administer a bolus of drug in a determined time and speed, to bridge the difference between
zero concentration and the chosen one. The bolus administered varies according to the
variation of concentration set; that is, for small variations (e.g. 1.5 to 2 μg/ml) it will administer
small doses, if we set large variations in concentration (e.g. 1.5 to 3 μg/ml) it will give more
substantial boluses. This will happen every time we intend to vary the concentration of the
drug to deepen hypnosis, up to induce sleep, or to increase it in case of BIS values too high
and raised or better than a Density Spectrum Analysis (DSA) and a SEF95 that indicate
inadequate hypnosis. To sum up: the TCI system to the effect always administers a bolus
every time we intend to make a variation and concentration upwards, and the boluses are
of a magnitude commensurate with the variation of concentration imposed.
However, even the bolus that is delivered to induce anesthesia, for example if we intend to
go from concentration 0 to 3 or 4 μg/ml to the effect, will always be quantitatively lower -
with the Schnider model - than what we commonly do with manual mode of 2 mg/kg. An
average dose of propofol to put a patient to sleep of 75 kg will be less than 100 mg and
obviously you will have to wait until the peak time of the drug (which for propofol is 2.5-3

22
minutes) to have a patient asleep. This modality, which administers small doses at induction,
is extremely respectful of hemodynamics and is safe and advantageous in compromised or
elderly patients, but it is slower and commonly we are not used or willing to accept such long
induction times. For this reason, TCI is not adequate for rapid sequence induction in patients
with a full stomach.
Once the bolus has been administered, the pump stops and waits for the drug molecules
administered to lead, through an increase in concentration in the central compartment and
a consequent diffusion in the effect compartment and therefore to an increase in
concentration at the effect site itself. After the bolus, when the effect concentration
approaches the set concentration (e.g. 3.2 μg/ml), with an almost equilibrium between V1
and Ve, the pump the pump starts working again at variable speed, taking into account how
much drug is distributed from the central compartment to the other compartments (V2 and
v3) and how much is eliminated (V0). The objective of the software and the pharmacological
model is to check the speed of the pump to continue to maintain the concentration that we
have selected stable, until we decide to change it. If we set an upward variation the pump will
deliver the usual bolus commensurate with the variation we intend to obtain, then stop briefly
and resume the variable speed infusion when we are at the desired concentration level in the
Ve. If, on the other hand, we change the concentration towards a lower value (for example
from 3.2 we go down to 2.8 μg/ml) the continuous infusion will be suspended (on the pump
we will read an infusion rate equal to 0 mg/kg/h) until, considering the distribution and
elimination of the molecules, the concentration in the plasma will not be lowered allowing
part of the molecules contained in the Ve to back-diffuse in the V1 according to concentration
gradient. This will give rise to a reduction of the concentration at the effect site with
consensual decrement of the pharmacodynamic action, so we will witness, for example, an
increase in BIS and a superficialization of the hypnotic plane. Once the concentration at the
effect site approaches that set by the anesthesiologist, the pump will restart working at
variable speed in the manner indicated above.
The TCI system will maintain progressively decreasing rates of administration over time
considering the accumulation of drugs, even for weeks or months, until we decide to stop
the infusion. For these reasons it would be the ideal system of sedation in intensive care
where over time, with prolonged administrations, you lose control of the dose administered
and the speed necessary to keep the "therapeutic" concentration stable, as well as the
possible accumulation of the drug and the time necessary for awakening.
The TCI systems do not consider any active metabolites, organ failure and tolerance
phenomena.
However, even in situations where there may be a wide variation of the mathematical
compartments and intraindividual variations over time as in the critically ill patient, TCI, by

23
administering proportional doses and varying the speed over time, certainly has superior
performance to the classic manual administration.
When at the end of the surgery we decide to wake up the patient we will bring the
concentration of the drug to zero without turning off the pump and, while this will stop, the
system will continue to calculate the progressively decreasing concentration of drug in
plasma (Cp), which will be followed by the decrement at the effect site (Ce). There will initially
be a fairly rapid decline, both in plasma and in the effect site, due to distribution in
neighboring compartments, but with time the decline will slow down due to the return of the
drug from the rapid and slow compartments to the central one. If the intervention lasted
many hours, at some point even to have small variations will take many minutes, because the
elimination of the molecules will be counterbalanced by the transfer of the drug accumulated
in the V3. All these times are calculated and predicted by the TCI system, which is able to
provide us with what we call decrement time - improperly also called awakening time - and
which is the time that will pass from when at the end of the intervention the target will be
brought to zero, then end of the infusion, to when the patient is awake. In practice, the
decrement time quantifies how many minutes it will take the concentration at the site effect
to move from the current target (for example 3.0 μg/ml) to a hypothetical target of awakening
or superficialization (for example 0.8 μg/ml), offering us an indication of when we can
reasonably stimulate our patient or hypothesize that he will open his eyes spontaneously.
The ideal target for awakening is set on the pump by the anesthesiologist, based on the type
of patient who falls asleep and his response to drugs in the induction phase. This means that
the decrement time with the Schnider model may be 1 μg/ml in young and healthy people
who have adequate metabolization capacity and have fallen asleep with a consistent dose of
hypnotic; while it will be more appropriate to set a decrement time of 0.8 μg/ml in elderly
patients, up to 0.6-0.4 μg/ml in compromised subjects. As we have already mentioned above,
the decrement concentrations to be set with the Eleveld+opioid model are higher
respectively 1-1.2 μg/ml in the elderly and 1.2-1.6 μg/ml in the young.
The setting of the decrement time is a particularly useful tool provided by TCI systems that
indirectly informs us about the depth of the anesthetic plan in progress, allowing us, in case
of exaggerated increases in the expected time for awakening, to lighten it by reducing the
target to avoid excessive accumulation.
The decrement time is also influenced by the other categories of drugs used during the
intraoperative - opioids, α2-agonists, benzodiazepines ... - so I can decide to reduce the
hypothetical concentration of awakening also considering these variables.
I recall that the concentrations of TCI systems are calculated on pharmacological models -
that is, on virtual patients - and are not values measured on the patient we are facing, so they
must always be used carefully and rationally. As already mentioned, the action of midazolam

24
tends to significantly prolong the decrement time. Also, for this reason in our hospital the
premedication administration of midazolam has been abandoned - replaced with satisfaction
by small boluses of 10-20 mg of propofol - and maintained only in the pediatric patient.
Despite its limitations, the decrement time allows to acquire a knowledge and control of the
various phases of anesthesia, as well as of the hypothetical pharmacological decay, which
manual systems and TIVA cannot even remotely approach. No other anesthesia delivery
system can provide this information for educational and organizational purposes.
The philosophy of TCI systems is that the desired concentration – suitable to protect our
patient from the insult he is about to suffer – is reached in the shortest possible time, avoiding
over - and underdosing and that this effective concentration is maintained for as long as
necessary, until we decide to replace this target concentration with a higher or lower one.
The TCI system can ensure this stability of concentration by rapidly and mathematically
correcting the concentration of drugs used for anesthesia, assuming that this stability is useful
for a good conduction of anesthesia.
A TCI anesthesia is an anesthesia that is always kept in the "therapeutic range": it follows
the variable phases of the surgical stimulus and prevents the repercussions in real time,
avoiding unnecessary and perhaps harmful variations in concentration. Remaining in the
therapeutic range means doing a dynamic and commensurate anesthesia, without incurring
sudden hemodynamic and depth changes in hypnosis that could have negative effects on
the outcome. An anesthesia of this type – beautiful to look at – also has an advantageous
meaning for our patient and is a good way of doing perioperative medicine.
TCI Dosage tips
Sedation
In the following pages, when we talk about targets, we will always mean the cerebral effect
site.
When filling out the anesthesiology record, the correct way to indicate the concentration at
the effect site is to put the word [E] after the name of the drug used. For example, in the case
of propofol I will write propofol [E] 3.5 .... 3.2 .... etc.; this way I am using a TCI infusion system
and the concentrations that are reported are at the effect site.

25
Sedation with propofol
 As we have repeatedly reiterated, the secret to obtaining good sedation and
maintaining adequate spontaneous breathing is the progression in steps to get to
the "right" target for the specific patient during and the specific procedure;
 Start with low concentrations: 0.5 μg/ml and gradually rise in steps, even at short
intervals of about 30 seconds - 1 minute, of 0.2-0.4 μg/ml until the desired sedation is
obtained (target of 0.7-0.9 etc.);
 Depending on the type of procedure and patient, good sedation is generally obtained
between 0.8 and 1.6-2.0-2.2 μg/ml;
 At target values above 2-3 μg/ml, especially if you get there quickly, you risk
spontaneous breathlessness or considerable respiratory depression, so it would be
better to always make small variations and wait for stabilization before imposing
further changes in concentration. Furthermore, targets between 2.6 and 3.2 μg/ml are
hypnosis maintenance under general anesthesia;
 For non-painful procedures (for example MRI) it is commonly possible to perform the
examination with average target concentrations between 1.6 and 2.4 μg/ml, in any
case the optimal target varies greatly from patient to patient and is very affected by
any associations (midazolam or opioids);
 In case of particularly painful procedures, if only propofol is used, targets of 4 μg/ml
or more can be slowly reached, with spontaneous breathing retention. However, it is
important: get there by incremental steps and always pay attention to respiratory
dynamics. As we know, in these cases, the limit between deep sedation and general
anesthesia is a very nuanced continuum and requires maniacal attention that only we
anesthesiologists can manage with tranquility;
 For long and painful procedures where there is conflict with the operator regarding
proximity to the airways (e.g. ERCP) and you need to keep your breathing
spontaneous, we prefer not to use opioids. Sometimes we even reach 5 μg/ml (always
for successive steps and keeping the breath spontaneous) and commonly when the
right level of sedation is found for that specific patient and that procedure, it is not
necessary to vary much the concentration that is usually fine until the end of the
procedure. Also consider using small amounts of ketamine 5-10 mg;
 In colonoscopies (very painful) it is best to associate an opioid such as fentanyl 100
μg. Sometimes average targets of propofol are up to 5-6 μg/ml; In these cases,
however, it is possible to assist the patient and ventilate him.

26
Analgo-sedation with remifentanil
 Start with low concentrations: 0.4-0.6 ng/ml and gradually rise in steps (at intervals of
about 1 minute) of 0.2 ng/ml until the desired level of analgo-sedation is obtained
(0.6-0.8-1.0-1.2-1.6 ng/ml etc.);
 Be very careful not to set large variations in concentration upwards (especially in
elderly and compromised patients), because the TCI technique to the effect always
gives a bolus, so the increase in small steps is mandatory;
 A good analgo-sedation, i.e., the tolerance of the invasive procedure in progress, is
obtained between 0.8 and 1.6-2.0-2.4-2.6 ng/ml. Consider that at the equilibria 2.5
ng/ml corresponds to about 0.07-0.08 μg/kg/min.
Sedation with the propofol-remifentanil combination
 The target concentrations of both drugs will be reduced, because the synergism of
the two drugs is very consistent;
 Increase the concentration in steps and slowly reach propofol 0.8-1.2-1.4 μg/ml and
remifentanil 0.8-1.6 ng/ml. With this association it is possible to perform an awake
intubation with fibrobronchoscope, or long and painful radiological procedures,
maintaining a good respiratory rate and a good arterial saturation and with great
satisfaction on the part of the patient.
 We emphasize once again that it is necessary to look for the right combination for
each patient always with a trend in small sequential steps, and in patients where the
risk of loss of breath could be dangerous this slowness in achieving the appropriate
targets is essential.

27
Dosage Tips for General Anesthesia
General anesthesia with propofol – remifentanil combination
Maintenance target:
 In this paragraph we refer classically for propofol to the Schnider model and for
remifentanil to the Minto model;
 Propofol TCI: 2.4-2.6–2.8–3.0–3.2-3.4 µg/ml (generally 3.0-3.2 µg/ml);
 Remifentanil TCI: 2.5–5 ng/ml (rarely 6–7-8 ng/ml).
We prefer never to use high concentrations of remifentanil, even more so in procedures
involving significant postoperative pain; Rather, we combine other fentanyl-type bolus
opioids in the classical way (100 μg before intubation, 100-200 μg before incision, etc.) or
sufentanil 10-20 μg and modulate the target of remifentanil to attenuate hemodynamic
changes.
Consider that 2.5 ng/ml is equivalent to the equilibrium approximately 0.06–0.08 μg/kg/min
of remifentanil and so 3.0-3.2 ng/ml corresponds to approximately 0.1 μg/kg/min.
How to conduct anesthesia with propofol and remifentanil in TCI
 Premedication administration of midazolam should be avoided if possible because
even low doses (1 mg) may interfere with the calculation of the decrement time for
propofol. Prefer to the administration of 10-20 mg of propofol just cannulated the vein
for anxiolytic purposes;
 Start with propofol at low targets 0.5-0.8-1.2 μg/ml; incremental steps in the
preparation phase, to sedate the patient while maintaining verbal contact;
 You can start remifentanil at low concentrations 0.4-0.6-0.8-1.0 ng/ml when we
are about to induce;
 It is debated whether to start the infusion of propofol or remifentanil first. Some prefer
to start with remifentanil claiming that it reduces the burning sensation felt by the
patient when injecting propofol into a vein. Probably at such low concentrations, the
question does not exist, and we prefer to start either with propofol because of its
sedative effect; or with both at low concentrations. Possibly, in case of small venous
accesses, you can precede the infusion of 20-40 mg of lidocaine;
 Progressively bring propofol to a target of 3-6 μg/ml for induction (higher values
for the young patient, lower for the elderly and the compromised patient);

28
 If we set high targets of 5-8 μg/ml we will administer a higher dose of propofol and
have a faster induction, at the expense of a greater hemodynamic repercussion;
 At the loss of verbal contact, or after a significant drop in BIS or Entropy values below
70–60, the chosen dose of muscle relaxant curare can be administered;
 At the same time increase the target of remifentanil to 2.0-3.0-5.0 ng/ml depending
on the patient's condition and make sure to have a target concentration of at least
3.0-4.0 ng/ml at the time of laryngoscopy to have complete protection from the
maneuver;
 Commonly, after 3-5 minutes, with concentrations of propofol at the effect site above
3.0-3.5 μg/ml there are hypnosis conditions that allow intubation (BIS below 55-50);
 Then remember to lower the target concentration to 3.4-3.2-3.0-2.8-2.6, which could
correspond to the maintenance concentration of hypnosis;
 Immediately after intubation lower the concentration of remifentanil because, while
awaiting surgical stimulus, plausible hypotension can be expected. A remifentanil
concentration of 0.8-1.2-1.4-1.6 ng/ml is sufficient to maintain the tracheal tube,
without the patient being disturbed;
 It is possible to prefer a more analgesic strategy, with a lower concentration of
hypnotic, always remaining at the apex of the isobolographic curve that covers the
tracheal intubation: considering laryngoscopy to be an intense pain stimulus, this
strategy is highly shareable. Target concentrations could be remifentanil 4.0-6.0
ng/ml with propofol at the effect site 2.0-2.5 μg/ml.
Isobolographic curves are the graphic expression of synergism between drugs acting on
different receptor systems, usually a hypnotic and an opioid, such as the propofol-
remifentanil or sevoflurane-sufentanil combination. The anesthesiological plan has the same
intensity at all points of the isobolographic curve, whether it is obtained with high
concentrations of opioid and low concentrations of hypnotic, or vice versa. What changes
instead, with these two alternative approaches, is the recovery time, which depends on the
kinetics of the drug and its sensitive context half-life: in fact, the awakening will be faster
using a low concentration of propofol, in favor of a higher remifentanil.
 At the time of surgical incision, make sure you have a propofol target between 2.8-
3.0-3.2-3.5 μg/ml (or an important remifentanil cover if you want to set a lower
propofol target);

29
 1-2 minutes before the surgical incision, increase the target of remifentanil to 2.5-3.0-
4.0-5.0-6.0 ng/ml depending on the expected pain stimulus, considering the clinical
condition of the patient and varying it in relation to the hemodynamic response;
 If other opioids are combined, e.g. 100-200 μg fentanyl or 10-20 μg sufentanil,
remifentanil concentrations should be reduced correspondingly and concentrations of
2.5-3 ng/ml should be achieved and not higher than both intubation and laryngeal
mask placement;
 Conduct anesthesia following the various phases of the operation, varying the
concentrations of hypnotic and analgesic as needed. Never go below a target propofol
concentration of 3.2-3.0-2.8-2.4 μg/ml, unless otherwise indicated by hypnosis depth
monitoring;
 Considering the values of decrement time especially of propofol as an indicator of
possible accumulation of the drug and to predict the awakening times: decrement
times for propofol greater than 15 minutes may indicate the need to reduce the target
concentration.
Each TCI pump manufacturer has set a different decrement target for propofol by
default, but in some cases, it is too high and should be modified by the
anesthesiologist. If you use the Schnider model it is useful to reduce the decrement
target to lower values such as 1.0-0.8-0.6-0.4 μg/ml, which allow you to have more
information on the hypothetical awakening time, i.e. the moment in which the patient
can be lucid and collaborative. When the target value for the decrement time is
reduced, there is understandably an increase in the time required for awakening, for
example if with a limit of 1.5 μg/ml the decrement time is 10 minutes, reducing it to 1
μg/ml I will observe that the time can increase to 20 minutes. This is because it will take
a longer time for the concentration of the drug at the level of the Ve, to fall to a lower
concentration than that previously set as an awakening target.
With 0.8-0.6 μg/ml almost all patients are commonly perfectly oriented and can leave
the operating room immediately; in the elderly especially if drugs such as midazolam
or dehydrobenzoperidol have been used, it is sometimes necessary to reach
concentrations to the effect of 0.5-0.4-0.3 μg/ml to have a shiny extubable patient.
When we use the Eleveld model for propofol (we always mean Eleveld+opioid) the
calculation of the decrement time is different and as the infusion proceeds the amount
of propofol administered, at the same set concentration, is lower than the Schnider
model. For these reasons, Eleveld can set decrement values higher than 1.0-1.5 μg/ml
in relation to the duration of administration, the age of the patient, his or her
comorbidities and the opioids and other adjuvants used. For short-term interventions
in young patients, awakening could occur at 2.0 μg/ml, while for prolonged infusions

30
in combination with an opioid such as sufentanil an awakening concentration is more
likely of 0.8–1 μg/ml, even more so in the case of frail or elderly patients;
 As far as remifentanil is concerned, the decrement time is irrelevant given its
extremely favorable kinetics; it is better to follow the needs of analgesia dictated by
intervention and hemodynamics. The default lower limit for remifentanil is 1.0 ng/ml
and we can leave it that way.
Recommended concentrations for sufentanil:
 Concentrations for non-cardiac surgery between 0.15-0.4 ng/ml;
 For cardiac surgery 0.4-1 ng/ml;
 Concentrations usually associated with spontaneous breath recovery: 0.1-0.2
ng/ml;
 On average, the target for the end of surgery, to be set as a decrement time, is 0.12-
0.18 ng/ml, with which there is a valid spontaneous breathing and an excellent
analgesia; consider the decrement time indicated by the model and the age to
schedule the interruption of sufentanil administration;
 We must keep in mind the age of our patient and the total amount of sufentanil
infused because this model (Gepts model) does not have correction covariates, that is,
for the same target it administers the same amount even in patients with different
weight or age;
 Sufentanil is not remifentanil so, despite having a good context sensitive half-life, it
has a time to peak effect – to be clear, a beginning of the pharmacodynamic effect –
after the bolus that exceeds 6-7 minutes; therefore, it is necessary to have a good
knowledge of surgical times and modify the target adequately in advance to prevent
the highlights of the surgery. Conversely, there is a risk of always being late and failing
to provide adequate analgesic coverage to our patient. In addition, it has a much
slower recovery due to its lipophilicity tends to accumulate more;
 Compared to remifentanil, which requires a careful analgesic transition, in
interventions with significant postoperative pain, sufentanil has a predictable analgesic
tail, with a known decrement time and a much better kinetics than fentanyl. Residual
analgesia is also good in very painful and long procedures, so the choice of sufentanil
may be an adequate alternative in cases where epidural, or other regional loco
techniques, are not viable.

31
Modern anesthesia is multimodal
It is based on the synergistic use of different molecules, which act on different receptors and
signaling pathways, to reduce the total dose of each, in order to exploit its useful effects
without paying the collateral and create a condition of hypnosis and harmonic analgesia.
Ideally, we would like to attenuate the activity of our patient's brain network, without turning
it off; reduce the state of alertness, also eliminating the painful stimuli that evoke it, with a
double action in concert that goes from the trunk to the cortex (bottom up) and vice versa
(top down).
For this purpose, and with a view to ERAS-Enhanced Recovery After Surgery, we have
introduced adjuvants in our general anesthesia:
• Clonidine is a less sophisticated α2-adrenergic agonist than dexmedetomidine,
but much less expensive, with a sedative and mildly analgesic effect, which acts by
inhibiting the release of norepinephrine from the Locus Coeruleus, which projects
to the thalamus, hypothalamus and diffusely to the cortex, thus reducing cortical
adrenergic tone. In addition, it enhances the effect of descending inhibitory
pathways by activating inhibitory interneurons, which take synapses at the level of
the posterior horns of the medulla and shield incoming painful afferents.
Classic dilution 150 μg/10ml and administration of refracted 30 μg boluses
throughout the operation. It favors better hemodynamic control and a softer
awakening: the patient who is not solicited and disturbed, with a dormant state of
alertness (wakefulness), will wake up only when his level of consciousness has been
perfectly reorganized (awareness). A hypnosis obtained with GABAergics creates
an imbalance of the system, with a relative excess of norepinephrine, which can
give rise to agitation and disorientation (especially in the case of inhaled
anesthesia and with low amounts of opioids); With α2-agonists, the balance axis is
brought back into balance because wakefulness and awareness are coordinated.
Let us remember that, for what has already been said, clonidine prolongs the
decrement time of propofol;
• Dexamethasone is a cortisone with several positive effects for intra and
postoperative: it reduces nausea and vomiting, relieves any edema of the vocal
cords, enhances the effect of opioids, local anesthetics and NSAIDs, but above all
inhibits phospholipase A2 and the arachidonic acid cascade that determines the
production of prostaglandins. Surgical trauma, in fact, triggers an inflammatory
response, with the production of mediators that bind to tissue nociceptors giving
rise to that type of burning pain, generally difficult to cover with opioids. For these
reasons, we administer 4-8 mg, depending on the patient's weight, during

32
induction (slowly, to avoid the annoying sensation of itching and burning groin-
genital);
• Lidocaine binds sodium channels blocking their entry, inhibiting the excitation of
nerve endings, and slowing the conduction of the action potential with a clear
antinociceptive effect, both in acute and chronic pain conditions. In addition, it
strengthens the sedative action of hypnotics.
It also affects NMDA, muscarinic and nicotinic receptors. In addition, it acts on the
degranulation of neutrophils, stemming the amplification of the inflammatory
response. Therefore, it reduces the amount of opioids needed during surgery and
in the following hours.
Recommended dosages range from 1.5 to 2.5 mg/kg to be administered as a
bolus, followed by a continuous infusion at 1-2 mg/kg/h, to be discontinued one
hour before the end of surgery. We generally prefer, for simplicity, to administer a
dosage equivalent to boluses: about 100 mg in bolus at the beginning of the
intervention, which we then repeat in the middle of the same and in closing.
It is important to remember that these dosages should be reduced in patients with
hepatic or renal impairment and that there is a risk of the toxic dose if exceededing
4-5 mg/kg or 300 mg total bolus;
• Ketamine acts as an antagonist of glutamate NMDA receptors: at the peripheral
level it prevents the propagation of the nociceptive stimulus to the posterior horns
and along the spinal cord. At the cortical level, it reduces the GABAergic tone
exerted on the pyramidal interneurons, creating the condition of known
dissociation between the thalamus-neocortex and the limbic system, with a
paradoxical increase in cortical electrical activity (the BIS increases due to the
appearance of high-frequency gamma waves in the EEG trace).
It is the main drug to avoid remifentanil hyperalgesia. By blocking the NMDA
receptor, it prevents the opening of the calcium channel and its entry into the cell,
which would lead to a lowering of the algic threshold and a lack of pain control
with opioids.
As an adjuvant it is used at low dosages, with a predominantly analgesic effect,
namely: 0.15-0.35 mg/kg (up to 0.5 mg/kg) bolus or 1-14 μg/kg/min in
continuous infusion. In practice, in a patient of 70 kg we administer 20 mg at
induction, which we then repeat at the incision and in the continuation of
anesthesia, when we see its usefulness. If we plan to pack a PCA pump or elastomer
with morphine, we typically also add 30-40-50 mg of ketamine depending on the
age and weight of the patient.
Low-dose ketamine (10-20 mg) is also endowed with neuroprotective properties
(antioxidant action of free radical scavenging, effect of central sympatholysis and

33
increased dopamine metabolism in the caudate) and, for these reasons, should be
considered in elderly and compromised patients, to improve the quality of
anesthesiology experience and reduce the risk of postoperative delirium.
Having antidepressant characteristics, it also has the pleasant effect of improving
mood.
It is recommended to administer 10-20 mg of ketamine also to facilitate the
positioning of the laryngeal mask, or even before intubation, avoiding excessively
high doses of propofol and/or opioids;
• Magnesium sulfate exerts its properties by blocking the calcium channels of
NMDA receptors; therefore, preventing the central sensitization that is the basis of
the painful memory that determines its chronicization. It has an additive-
synergistic effect with ketamine. It decrements the release catecholamines and
thus sympathetic activation, reducing peripheral nociception, stress response to
surgical stimulus and blood pressure. It enhances the action of hypnotics by
reducing arousal and has a deep muscle relaxation effect which exacerbates that
of muscle relaxants.
30-50 mg/kg is indicated as a bolus-laden dose, followed by a continuous infusion
at 6-20 mg/kg/h until the end of surgery. However, even the single bolus at the
beginning of surgery guarantees effective postoperative analgesia, resulting in a
reduction in opioid consumption up to 24 hours after surgery. For convenience,
we dilute 2 g of magnesium (suitable dose for a patient of 70 kg) in 100 ml of
saline, which can be administered as a slow bolus during the first hour of surgery.
• Intrathecal or antalgic spinal morphine - supported by an ERAS strategy -
consists in the preoperative administration of 0.1-0.2 mg of morphine: a simple
and minimally invasive maneuver that can guarantee excellent postoperative
analgesia lasting even longer than 12 hours (according to the literature up to 36
hours of analgesia). The most frequently described side effect is itching, but it
tends to appear at higher doses, i.e. above 0.15 mg, nausea, and the risk of
respiratory depression occurs for doses exceeding 0.2 mg.
Very advantageous also in the management of postoperative pain after caesarean
section, as the administration of 0.1-0.125 mg of morphine is sufficient to offer a
good analgesia to the new mother, freeing it from any elastomer.
As for the preparation, the simplest way is to dilute a 10 mg vial of morphine in a
drip of 100 ml of saline, thus obtaining the concentration of 0.1 mg/ml, from which
you will take sterile the dose you consider appropriate to administer, 1 or 2 ml
maximum.
There is no doubt that anticipating the algogenic stimulus in a timely manner brings
advantages for the patient, both intraoperatively and in the hours and days following. To

34
clarify we mean: the right dose, of the most suitable drug, at the appropriate time. Because,
probably, under anesthesia being perfectible has a meaning.
Exceed with opioids with a long half-life at the beginning of surgery "because there is so
much time", rise excessively with the concentrations of remifentanil “because it does not
accumulate anyway" and maybe suspend it to the patient still intubated is a superficial
wrong strategy. And it is likewise an error leave unchanged for hours an anesthesia as if a
surgery were not a dynamic condition in which the body - and mind - of our patient is
participating… Body and mind that will remember having had pain, even weeks later, even
if they will not know that it happened.
Preventing the imposition of pain and anticipating it along the signal pathways that are
known to us, going to meet them with all the weapons at our disposal and taking care of
the patient's well-being in a holistic way will positively impact their perioperative
experience and reduce the risks of chronicization of the same.
 It is essential to predict and plan in time the analgesic transition which, depending on
the type of patient and surgery, and in the absence of central or peripheral nerve
blocks, must be multimodal and consider the pharmacodynamic peak time of the
chosen analgesic:
• morphine 0.05-0.15 mg/kg bolus IV 30–45–60 minutes before the end of surgery;
• or, as an alternative to morphine, tramadol 100 mg 45 minutes before the end of
surgery;
• paracetamol 45 min before the end of surgery;
• Ketorolac 15-30 mg 45 min before the end of surgery.
Morphine (or tramadol) and paracetamol should be used in combination because they act
on different receptors for better post-operative analgesia; in addition, the use of
Paracetamol and NSAIDs reduces the consumption of opioids and therefore the associated
side effects;
 At the end of the surgery, pay attention to the decrement time of the drugs used,
predicting, however, a slower awakening than an anesthesia conducted with
desflurane. It is possible to start reducing the target of propofol in time to lower values
(2.5-2.0 μg/ml), which allow to bring to decrement times not exceeding 5-10 minutes
during surgical wound closure;
 Maintain the target of remifentanil even at target values of 1.5-2.5 ng/ml up to the
last stitch, then reducing them to targets that guarantee analgesic protection from the

35
tracheal tube (1.2–0.8–0.6 ng/ml) that minimizes the risk of coughing but allows the
resumption of spontaneous breathing.
Proposal for general anesthesia with propofol, sufentanil and
remifentanil
We mistakenly thought, over the years, that having two extremely powerful and rapid drugs
such as propofol and remifentanil we could currently manage anesthesia by varying the
concentration of these two molecules as needed. If we had needed more hypnosis, we would
have increased propofol and if there had been a need for greater analgesia, we could have
increased remifentanil ad libitum.
Nothing we do is without implications and disproportionately increasing hypnosis and/or
analgesia - too much of good things - can lead to unfavorable regulations triggered by
homeostatic mechanisms.
It might seem to be in contrast with the strategies currently in fashion (opioid-sparing and
opioid-free), to propose a general anesthesia that combines the use of two opioids such as
sufentanil and remifentanil. In fact, in almost all the world where TCI is done with propofol
and remifentanil, fentanyl administration is often combined, perhaps in a small dose.
The first reason is that to have a perfect control of surgical stress with only remifentanil, in
the absence of central and/or peripheral blocks, there may be the need to use very high
concentrations, higher than 6-8-10 ng/ml (in TIVA 0.2-0.3 μg/kg/min), which inevitably
involve the activation of pro-nociceptive systems with the risk of acute postoperative
hyperalgesia. In addition, the punctual coverage of analgesic needs, without chasing the
surgical stimulus with a bolus administration, allows a sure saving on the total dose of opioids
and determines in fact an effective sparing.
What we are looking for is a sartorial and dynamic anesthesia, sewn on the patient and
modeled on surgical timing.
The second reason is that the simultaneous use of propofol-sufentanil-remifentanil
allows an extremely punctual control of surgical stress and guarantees conditions of
stability of the anesthetic plane that cannot be obtained in any other way. This
intraoperative stability has the property of being reflected in a state of greater postoperative
well-being and is so appreciated by anesthesiologists, which has led in a short time to the
use of this modality by all the anesthesiologists of our group.
The simultaneous administration of two opioids in TCI is based on the different
pharmacokinetics of the two molecules: remifentanil drug extremely rapid with TTPE of about
1 minute, but which lacks the desirable analgesic tail in the immediate postoperative period;

36
sufentanil drug slow in variations, with TTPE of 6-8 minutes, but with a notoriously longer
decrement time and therefore sufficient predictable analgesic tail, adequate almost an hour
after extubation.
Their combination allows to administer a concentration of sufentanil base, such as to ensure
the desired intraoperative analgesic tone and guarantee a congruous postoperative
analgesia; while remifentanil has the role of controlling, both upwards and downwards, the
rapid and extremely variable need for analgesic coverage dictated by surgical stress
conditions.
The coordinated use of these two opioids allows an extremely precise control of anesthesia
and the various surgical phases - not reachable with only one of the two - using low targets
of remifentanil, always below 6 ng/ml, concentration considered at risk of hyperalgesia.
This scheme allows to further lower the maintenance concentrations of propofol, as the
synergism between the three drugs and in particular the partially hypnotic profile of
sufentanil is exploited.
Treviso Method version 2022
General anesthesia with THREE TCI pumps
Some indications on how to do it:
 It is essential to position the pumps in a standard way to avoid fixing errors.
The choice of our group provides that propofol should always be positioned at the
bottom, sufentanil (with a strong hypnotic effect synergistic with propofol) in an
intermediate position, remifentanil above all because more properly analgesic and
context insensitive.
So, suggested standard arrangement:
3 Remifentanil - Eleveld model
2 Sufentanil - Gepts model
1 Propofol – Eleveld+opioid model
 Start with propofol in steps to induce pre-intubation sedation, propofol 0.6-0.8-
1.0-1.2 μg/ml;
 Concomitantly start with sufentanil at concentrations 0.1-0.2-0.3 ng/ml;
Considering the slow achievement of the plasma-biophase balance of sufentanil of
about 6-8 minutes, it is possible to immediately set the concentration to 0.3 ng/ml
which could be suitable for protection from laryngoscopy without risking opioid
rigidity;

37
 Then start remifentanil at low targets 0.6-0.8-1.0-1.4-2.0 ng/ml in the phase
preceding administration of the chosen neuromuscular blocking agent;
 About one minute before intubation, we can administer 10-20 mg of ketamine to
allow a more complete and adequate control of stress associated with
laryngoscopy;
 At intubation the concentrations of propofol could be 2.0-2.5-3.0 μg/ml, while that
of sufentanil 0.2-0.3 ng/ml and remifentanil depending on the needs and
hemodynamic conditions 2-3 ng/ml;
 After intubation, adjust the concentration of propofol to the desired BIS value, or
rather on the appropriate hypnotic level, then lower remifentanil to 0.8-1.2 ng/ml,
lower sufentanil to 0.2-0.1 ng/ml;
 Continue maintenance with propofol on the indications of hypnosis monitors and
remifentanil on sudden changes in surgical stress; Sufentanil target concentrations
can be maintained more stable at 0.25-0.2-0.15 ng/ml by controlling the desired
decrement times based on the patient's age and clinical condition and the
expected duration of surgery.
This anesthetic strategy is recommended for surgeries with a high algic component, for which
high postoperative pain is expected and there are no possibilities to control pain with loco-
regional techniques (for example laparotomy with contraindication to epidural placement).
The stability of the anesthetic plane obtained with this combination has been so appreciated
by Treviso anesthesiologists that the three-pump mode is now used in a standard way, even
with epidural and/or antalgic spinal in progress or wall blocks.
Intraoperative control and stability – sufentanil has a low hemodynamic impact unlike
remifentanil – and postoperative analgesia are generally very satisfactory, with extreme well-
being for the patient upon awakening, difficult to achieve with other anesthesiological
techniques.
General anesthesia with FOUR TCI pumps
A fourth pump with dexmedetomidine at concentrations of 0.1-0.2-0.3 ng/ml is added.,
correspondingly reducing propofol maintenance concentrations as a guide to hypnosis
monitoring. In the case of prolonged interventions, considering the very long decrement time
of dexmedetomidine, it is prudent to suspend administration even one to two hours before
the end of the surgery, to avoid a too slow awakening, conditioned by the accumulation of
the drug.

TCI practical Tips for use 5ed June 2023.pdf

TCI practical Tips for use 5ed June 2023.pdf

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