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Total Intravenous Anaesthesia:
The far-from-definitive guide
Harry Murgatroyd and Frank Swinton
Airedale NHS Trust 2012

Introduction
Our aim in producing this booklet is to help bridge the gap between watching
someone who’s good at TIVA and having a go yourself. We remember this as
being a big, scary thing to do and we wished that there was more practical
advice available. Theoretical information about the pharmacoblahblah is easy
to come by but we feel that a real, practical ‘beginner’s guide’ to TIVA might be
of use.
We’ll look a why you might want to use TIVA at all, what the potential
problems are, and which patients it might be unwise to use TIVA on. Then
we’ll have a look at a practical guide to actually doing TIVA, followed by some
illustrative case studies.
This booklet is, of course, no substitute for appropriate background knowledge
and training and must not be used as a ‘recipe book’ for TIVA. We do hope
however that you will find it a useful guide to answering some of the common
worries and then an aide-memoir when you haven’t delved into TIVA for a few
months and suddenly have a patient who would benefit from a superior
anaesthetic.
Introduction..........................................................................................................2
1
 Why TIVA? ......................................................................................................3
2
 Why Not TIVA?...............................................................................................5
3
 An introduction to practical TIVA ..................................................................7
Introduction to the cases:...................................................................................12
1
 Conscious sedation during spinal anaesthesia .............................................12
2
 Awake fibreoptic intubation .........................................................................14
3
 An oesophagectomy in an obese lady ...........................................................16
4
 Another case…...............................................................................................19
5
 The Full Monty: A gynae laparoscopy ......................................................... 20
Fortune favours the brave… TIVA for the connoisseur .................................... 24
The super-condensed, Airedale only, beginners guide to TIVA ....................... 26
Summing up....................................................................................................... 30
Models to play with............................................................................................ 30
References.......................................................................................................... 30

1 Why TIVA?
1.1 PONV
Because propofol has its own, intrinsic, anti-emetic properties and because
remifentanil is eliminated from the plasma so quickly, the incidence of PONV
in TIVA patients is very small. As shown in the IMPACT study below, the
incidence of PONV after an inhalation anaesthetic increases with the length of
exposure whereas the incidence with TIVA is low and not influenced by the
length of the anaesthetic. If patients get sick after TIVA, it’s probably due to
the long-acting opioid analgesics they’ve been given in recovery, rather than
the anaesthetic. IMPACT showed a 25% risk reduction by the use of TIVA
rather than inhalational anaesthesia, and this 25% would be in addition to the
reduction given by other antiemetics.
1.2 Fast emergence
The half-time of remifentanil is approximately four minutes and this is not
context sensitive. Twenty minutes after you turn off the pump, there is
essentially no remifentanil remaining in the plasma. Propofol does accumulate
in fatty tissues but with a bit of practice, it’s possible to turn down the rate of
infusion towards the end of a case to minimize emergence time. Recovery
should no longer be a place where people languish for several hours drifting in
and out of sleep and being sick, it should be a parking bay where awake
patients demonstrate their cardiovascular stability while the ward bed/trolley
is fetched.
1.3 Stability
The cardiovascular stability of a TIVA anaesthetic makes for extremely boring
chart recording. This is particularly useful for surgeries where there are
periods of little stimulation interspersed with periods of profound stimulation
such as ENT surgery.

1.4 Stimulating surgery
Because of the profound analgesic effects of remifentanil, even the most
stimulating procedures (such as awake fibreoptic intubation or endoscopic
sinus surgery) can be performed without having to have the patient so ‘deep’
that they become cardiovascularly compromised.
1.5 Diabetes
Nicholson (see references) recommends avoiding volatiles in diabetics because
they inhibit residual insulin secretion whilst opioids are beneficial because
they decrease catabolic hormone secretion. TIVA is therefore an obvious
choice for ‘brittle’ diabetics.
1.6 Environmentally friendly
Because TIVA doesn’t use any volatile agents at all, its environmental impact
is probably smaller than that of a vapour anaesthetic. The vapours and N2O
are approximately equal contributors to the greenhouse effect (see paper by
Shine) and therefore the more we use of each one, the larger the
environmental impact (6l.min -1 of 7% desflurane in 70% N2O is NOT cool).
TIVA is especially popular in Australia and New Zealand because of the
significant ozone depleting potential of volatile (CFC) agents.
There is, of course, a carbon cost involved in the manufacture, transport and
disposal of TIVA drugs, pumps, syringes etc but this is difficult to quantify
because pharmaceutical companies don’t tend to publish their carbon
footprints in the public domain. There is also concern about the effect of
propofol on marine life, though again, this is difficult to quantify.
1.7 Genetic Problems
Neither propofol nor remifentanil are triggers for malignant hyperpyrexia or
porphyria.

2 Why Not TIVA?
2.1 It’s much more expensive
Now that both remifentanil and propofol are ‘off license’ and generic versions
are available, the cost compared with a vapour anaesthetic is not a huge issue.
Certainly, if a patient has to stay in hospital overnight due to PONV then the
cost of a TIVA anaesthetic is negligible in comparison.
2.2 It’s too much faff
Only at first! We suggest starting with cases which are predicted to last a
couple of hours so you have plenty of time to get settled and maybe even draw
up drugs for the next patient while the first one is still asleep. You’ll quickly
get into a routine and will then realize that it really isn’t much more effort.
2.3 They’re always hypotensive
This is a common problem, especially in hospitals without depth of
anaesthesia monitoring. It comes from our fear of awareness so we tend to
overdose our patients because we don’t know ‘how asleep’ they are. At first,
have a syringe of metaraminol to hand and with experience and/or depth of
anaesthesia monitoring, you’ll come to see that they don’t all have to be
hypotensive all of the time.
2.4 Who not to use TIVA for
Sadly, there are limits to the wonders of TIVA. It is not suitable for use in
young children and it should be used with caution in the very elderly or the
very sick. These groups of patients were not included in the sample
populations used to devise the models and there is some evidence that the
models are inaccurate at the extremes of age. The Marsh model excludes
children under 16 years of age - this is why you have to put in the patient's age
at the beginning, it's not used in the model itself! There is a paedfusor model
that can be used; we have no experience of using this. So that’s the end of
that…
The elderly tend to have slow circulation times and a relatively small volume
of distribution leading to much higher plasma concentrations than the model
predicts. This of course is doubly bad news because not only do they need less
hypnotic agent than younger patients, they often don't have the cardiovascular
reserve to maintain a blood pressure.
Septic or collapsed patients will also behave in a manner which is
unpredictable and doses should be dramatically reduced to start with in order
to avoid circulatory collapse. I wouldn’t recommend using a propofol TCI in
such a patient anyway, but the same limitations apply to remifentanil
infusions.

2.5 So many numbers… a major stumbling block.
- mg.ml -1 / µg.ml -1 concentrations of drugs
- µg.ml -1 / ng.ml -1 plasma concentrations (target, plasma and
effect site calculated)
- ml.hr -1 / µg.kg -1 .min -1 infusion rates
- µg.kg -1 bolus doses
The reason for all the different numbers is that it depends which system
you’re using and what you’re trying to do. This brings us on to what to do and
how to do it…

3 An introduction to practical TIVA
3.1 Propofol TCI
For propofol, the concentration is (almost always) 1% which is 10mg.ml -1 . We
do not recommend running propofol as a simple infusion (for instance using
the Roberts 10,8,6 regime) because it is difficult to do well and easy to over or
under dose patients.
Propofol Target Controlled Infusion (TCI) can target either plasma
concentrations or effect site (brain) concentration. Most pumps require you
to enter a target plasma concentration (Cpt) and then display calculated actual
plasma concentration (Cp) and calculated effect site concentration (Ce) all in
µg.ml -1 . As the infusion continues, the plasma and (more slowly) effect site
concentrations should all increase exponentially to reach the target plasma
concentration that you have entered.
3.2 Remifentanil
Remifentanil is not quite so straight forwards paradoxically because it is such
a good drug. It is cleared so quickly that it can be given on a µg.kg -1 .min -1
basis rather than as a target controlled infusion.
3.2.1 Manually controlled (µg.kg -1 .min -1 ) infusion
GSK who held the original license for remifentanil (as Ultiva) used to give out
cardboard calculator wheels not unlike obstetric due-date calculators. You
entered the concentration of remifentanil (usually 50 µg.ml -1 which equates to
a 2mg ampoule diluted in 40ml saline) and the patient’s weight and were then
presented with a suggested range of pump speeds (ml.h -1 ) which would relate
to an infusion of remifentanil on a µg.kg -1 .min -1 basis. Frustratingly there
seemed to be a black-hole somewhere which meant that there was never a
cardboard “wheel-of-fortune” when you wanted one. Thankfully they are now
available digitally online for your phone for less than the cost of a coffee. FS
uses iRemi. In order to accelerate the time taken for an increase in infusion
rate to reach a plasma/effect site steady state, it is often a good idea to give a
bolus of remifentanil. Without boluses, in a 70 kg, 170 cm, 40 year old male
steady state plasma concentrations will be reached after 25 minutes at
infusion rates between 0.25 and 0.5 µg.kg -1 .min -1 . So it is advisable to use
initial boluses. iRemi suggests bolus sizes (ml), alternatively,
0.5 µg.kg -1 as a bolus over ten to fifteen seconds is a good place to start. Fast
boluses of remifentanil tend canto cause bradycardia and/or chest wall
rigidity.
As an alternative when faced with a lack of suitable equipment, Lesser
recommends a simple calculation approach:
Prepare remifentanil to a concentration of 60 µg.ml -1 (2 mg diluted to
33.3 ml). Divide the patient’s body weight in kg by 10. This gives the
rate in ml.h -1 to deliver 0.1µg.kg -1 .min -1 .

This will enable you to use simple syringe drivers, all-be-it with a more
concentrated solution of remifentanil.
3.2.2 Plasma / Effect effect site targeting
If you have the luxury of two TCI pumps (at Airedale the Alaris PK pumps)
and wish to use one for remifentanil then the principle is the same as that for
propofol except that target plasma and effect site concentrations are given in
ng.ml -1 .
When using TCI there is no need to manually programme a bolus, the pump
will do it automatically when you programme an increase in plasma
concentration target. Remifentanil blood concentrations (ng.ml -1 ) estimated
using the Minto (1997) pharmacokinetic model, and a further estimate is
made of the effect site concentration.
3.2.3 Which method is preferable / superior – manual infusion or
targeted infusion?
To help with putting the idea of the two models together, and to give you an
idea of equivalences, look at the following table and figure. Bear in mind
though that with a manually controlled infusion, without boluses it will take
about 25 minutes to get the plasma
Remifentanil Infusion
concentration to the steady state level
Rate (µg.kg
shown below.
-1 .min -1 Remifentanil Blood
)
So which is better? Plasma level targeting.
0.05 1.3
0.10 2.6
0.25 6.3
0.40 10.4
0.50 12.6
1.0 25.2
2.0 50.5
Concentration (ng.ml -1 )
Of course, this isn’t to say that you can’t use manual infusions, but there are
advantages to target controlling. For young, fit patients a manually controlled
infusion will give a reliable estimate of the plasma levels (as shown above)
and the patient should be able to cope if it is actually a bit higher than your
estimate. In elderly or sick patients, the plasma level can be much higher than
you think and these are also the patients who can’t cope with high levels as
well. The Minto model shows that Remifentanil pharmacokinetics are
dependent on the weight, height, age and sex of the patient. So if you use

manual controlled infusions for this sort of patient, reduce the doses you give.
Or just use the model that will calculate it all for you.
An example;
If you took a tall 21 year old woman and a short 80 year old woman,
and gave them a bolus and started them on a typical manual 0.25 mcg/kg/mn
infusion, after about 15 minutes the difference in plasma levels could be 5
ng/ml vs 8 ng/ml respectively.
What is becoming clear, however, is that if your TCI pump offers you the
option of effect site targeting with Remifentanil, then it probably isn’t worth
using it.
3.3 Actual weight, lean body mass or ideal bodyweight?
The excellent article by Baerdemaeker indicates that this is difficult for
propofol because different studies have made different conclusions.
Essentially, in a fit person, use the actual body weight but in an elderly or
unwell person, use the ideal body weight plus 0.4 of the excess weight.
Ideal body weight (kg) = height (cm) – x (where x=100 for males and 105 for
females)
For remifentanil use the ideal bodyweight (plus a bit if you’re losing your
nerve). The TCI remifentanil pumps calculate this for you.
The issue of obesity is covered in more detail in one of the case scenarios.

3.4 Danger!!
These are the things to beware of in the world of TIVA, above and beyond
what you should be doing anyway.
3.4.1 The drugs
No
remifentanil
Wrong dose of
remifentanil
Solution too
strong; delays
in induction,
and
inadvertent
apnoea
3.4.2 The equipment
I’ve done, he’s done it. You get distracted, you forget. If there
is any doubt, thrown it away and start again.
It comes in 1 and 2 mg vials; so easy to have a cock up. My
solution – only ever use 2mg vials. But even then your ODP
can get the wrong one, so always check…
Earlier on, we advocated using a 60 mcg/ml solution as a
dodge around not having the right pump. There are three
problems with this. Firstly, if you always use the same
concentration of remifentanil, you will get familiar with the
rough infusion rates that are in the correct ball park. If you
then use different concentrations, this distracts from that
final ‘does it make sense’ check. Secondly, the more
concentrated solution can sit in the Y connector (as discussed
shortly) and have a good dose of remifentanil that you can
then render the patient apnoeic with. Thirdly, a more
concentrated solution will be infused more slowly. If there is
dead-space or slack in the drive of the syringe pump, then
your drug will not be being delivered as you think.
Three way taps It is good practice to attach a three-way tap to the syringe
that you are giving the drug from. When the syringe runs
out, you can close the tap, preventing…
Siphoning …the inadvertent continued infusion under gravity, along
with a bolus of air when you reconnect.
Backflow
Dedicated
cannula
If you don’t use non-return valves, your drug can pass
back up your Hartmanns line attached to the same
cannula, and you can give an inadvertent bolus. Another
way around this is…
One for TIVA, one for fluid + drugs.
Disconnection A potential disaster – the patient is not anaesthetised and
you will have to abandon your TIVA as the figures will not

Keep your
cannula visible
Dead space
reflect reality. So…
If you haven’t filled the dead space in the octopus, the
computer will think that that drug it has given has gone to
the patient, which it hasn’t. Also you might be tempted to
intubate or some-such before they are ready.
Wrong model Oh – this is a beauty! Load up a remifentanil syringe and
stick it in a pump. Tell the pump it is propofol and watch
your world collapse with a truly massive initial dose of
remifentanil. Check, check, and check again.
Wrong syringe
Drug left in the
octopus
3.4.3 The patient
Drinkers, the elderly,
the obese
This will also make your figures meaningless. The syringe
recognition system on the pumps is only so good. You
have to check. I have seen it choose the wrong brand of
syringe on many occasions.
You’ve finished, disconnected, in recovery. The nurse
gives some tramadol and the patient stops breathing.
Remifentanil in the octopus. Has happened twice at the
LGI (admittedly with children).
BEWARE; all the models are based on small
numbers of average patients. If the drug clearances
are different due to the patients alcoholism, or their
body compartments are different because of their
morbid obesity, the figures you see will not be what
is going on in the patient. HM has had one patient
who he sorely regretted using TIVA on – the
patient was a drinker, but more than she had let on.
The amount of propofol used was… um…
ridiculous.

Introduction to the cases:
The rest of the booklet is given over to example cases. We’ve started simple
with propofol TCI sedation and then remifentanil to facilitate awake fibreoptic
intubation, getting more complex, to end at propofol/remifentanil TIVA for
major surgery. Suggested doses are given as a starting point but should not be
followed blindly as a recipe.
We also use different techniques. For remifentanil infusions, HM uses target
controlled infusions and FS uses manually controlled infusions. We have left
both techniques in the cases as it illustrates the difference between the
methods, and may help when you can’t give a target controlled infusion
because someone has already nicked the pump.
1 Conscious sedation during spinal anaesthesia
The patient is an 85 year old male, past medical history of hypertension and
gout, who presents for a TURP. You persuade him to have a spinal
anaesthetic, but he requests sedation during the procedure.
You remember seeing someone use a blood targeted propofol infusion for just
such an operation in the past, and think that you will attempt the same.
1.1 What are the three main advantages of propofol TCI over
the alternative drug, midazolam?
1. Titratability
2. Steep dose response curve for both drugs but propofol wears off more
rapidly
3. Clear and rapid recovery of full consciousness
Midazolam takes ages to work, by which time you’ve given some more. Then
the two doses together are too much and the patient is anaesthetised. There is
also the usual interpersonal and age related variation in sensitivity to both
these drugs. At least with propofol it doesn’t last as long, and you have the
reassurance of an estimated plasma level for that patient based on their age
and weight.
Propofol TCI is a good technique for this sort of anaesthetic; there are no
analgesic requirements intraoperatively or postoperatively, so no need for
other drugs that may interact and lead to inadvertent unconsciousness.

1.2 What would be a sensible starting level for your infusion
and why?
I would still use a target controlled infusion for this sort of sedation, even
though the infusion rates used are low. Compared to remifentanil, propofol
dosing is not as intuitive and rapidly reversible if you get it wrong.
The usual dose range is between 0.5 and 1 µg.ml -1 . That said, your patients
may be old and sensitive, and remember that they’ll often fall asleep with just
the spinal in. I have had an 85 year old on the table who was difficult to rouse
on a plasma level of 0.5 µg.ml -1 , and he eventually ended up being comfortable
and rouseable on a target of 0.1 µg.ml -1 .
1.3 Which pharmacokinetic model would you use?
At this sort of plasma level, there would be little practical difference between
the models. We will cover this in more detail later, but suffice it to say that the
Schnider model will give a slower initial bolus of propofol. It is therefore quite
appropriate to use in the elderly and in those who you do not want to lose
consciousness.

2 Awake fibreoptic intubation
You are anaesthetising for orthopaedic surgery and there is a 35 year old lady
on the list for a wound washout. She had an ORIF humerus two weeks ago but
has now developed pain and raised inflammatory markers. The surgeons
would like to ensure there is no collection in her arm, and because they are
concerned about compartment syndrome, they have asked you to avoid
regional techniques.
On the day ward she is extremely anxious and tells you that the anaesthetist
came to see her after her previous surgery to tell her that she had been a
difficult intubation. She is slightly obese but otherwise well and is just getting
over the sore throat of last time. On examination she has all her own teeth,
4cm of mouth opening, Mallampati grade II view with a big tongue and good
neck movement. She weighs 80kg.
In the notes, sure enough it is well documented that despite a moderate
looking airway, and sufficient relaxation, it took two Consultants an hour to
intubate her last time and she required dexamethasone to minimise swelling
and an overnight stay to ensure that there was no laryngeal trauma or lasting
oedema. An awake fibreoptic intubation is clearly the best option for this lady.
You have some experience with the fibrescope but not so much in awake
patients and she is very keen that she doesn’t die and/or have the same sore
throat as last time.
The technique of awake fibreoptic intubation is beyond the scope of this
booklet but suffice it to say that at a remifentanil infusion rate of 48ml.h -1 of
50 µg.ml -1 (0.25 µg.kg -1 .min -1 ) she remains awake and compliant but tolerates
the intubation with no coughing or gagging. Her heart rate remains stable at
50bpm and sats never fall below 95%. At the end you extubate her “awake”
shortly after turning of the remifentanil. She has no sore throat and thanks
you profusely for “the best anaesthetic she’s ever had”.
2.1 Why not midazolam?
Midazolam or other agents don’t have the same rapid on/off effect or the
profound airway reflex obtundation without significant sedation that
remifentanil enjoys.
2.2 Do you still apply local anaesthesia to the airway?
Yes. It’s easy to do and will improve your chances of success. It also means
that you’re not relying solely on remifentanil.
2.3 Why not just use local anaesthesia to the airway?
This can be done but can be unpleasant and can be difficult to get good cover
to the whole airway – there can be troublesome bare patches. A recent case
series was published that conversely used just remifentanil for AFOI. I
wouldn’t recommend this either – they used large doses and had patients
stopping breathing. The middle road of local anaesthesia with remifentanil to
help you out with missed bits and light sedation is probably the way to go.

2.4 I’m worried that the patient will loose consciousness or
stop breathing while I’m concentrating on the fibrescope.
You’re right to worry! The best solution is to “start low and go slow” with the
remifentanil. You’re aiming for a situation where the patient is responsive and
will talk to you but is nice and relaxed. You may have to remind them to
breathe if their oxygen saturations start to fall. We find supplementary oxygen
administered via a nasal sponge into the other nostril is useful.
NAP4 recommended that two anaesthetists are present for AFOI because of
the potential to stop breathing and desaturate. It is difficult to monitor the
patient whilst you are holding the scope and navigating the airway.

3 An oesophagectomy in an obese lady
You are presented with a 55 year old lady for an elective laparoscopically
assisted oesophagectomy for adenocarcinoma. She has an HDU bed booked
for her post-op recovery, and the consultant has talked to her about having a
thoracic epidural prior to induction. She is a little on the obese side, with a
BMI of 40.
The epidural is duly accomplished, and the anaesthetic is started. A
remifentanil infusion is started, the patient is induced using a propofol bolus,
and the consultant intubates with a single lumen tube. He then turns on the
desflurane.
3.1 What are the advantages of using remifentanil in this
case?
For this case, an epidural has been sited for post-op pain relief, but the surgery
itself will involve stimulation at sites not covered by the block (airway, lower
abdomen). Also, you might not want to bolus your epidural at the start of
surgery so that you can avoid the haemodynamic effects just before the
pneumoperitoneum and changes in patient position. Remifentanil is ideal as
all areas will be covered intra-operatively, and when the remifentanil is turned
off on completion, the epidural will provide the analgesia in the area of postop
pain. The lack of systemic opiates still knocking around the bloodstream is
of advantage to this patient post-operatively; respiratory complications due to
under-breathing because of opiates or inadequately controlled pain are a
major cause of morbidity in these patients. As she is also obese, this will
further compound these issues and would make using remifentanil even more
advantageous.
3.2 You put the patient’s height and weight into your
remifentanil TCI pump, and it will not let you enter those
figures. It lets you enter the height, but then will not allow
you to go up to the weight that you want to enter. What
are we going to do?
Remifentanil blood concentrations more closely correlate with lean body
mass, so you could use that instead. This is what the TCI pumps do for you,
and why they ask for height and weight. And that is why the pump won’t let
you enter that weight. You have told it how tall the patient is, and it has
calculated how high it will let you set the weight before the formula it is using
becomes useless (as the actual weight increases beyond this point, the LBM
starts to decrease – obviously it doesn’t actually, its just a quirk of the formula
used). So, what you could do is run the model with that maximum weight it
has let you put in. The levels in the patient will not be as high as you think they
are, so you will have to up your targets a bit. As a pre-warning, for men, a BMI
of between 40 and 45 will likely cause this problem with the TCI pump; for
women, between 35 and 40.

Or you could abandon the TCI method and use the manually controlled µg.kg -
1 .min -1 method, using the actual weight of the patient. This would overdose the
patient (blood levels much higher than you think they are), but remifentanil is
very titratable with a short decrement time so you could turn it down a bit if
there were problems.
3.3 Why has the consultant decided to use a volatile
anaesthetic rather than propofol TCI?
This is question about propofol and its pharmacokinetic models used in TIVA
pumps. You may be surprised to know that the Marsh and Schnider models
were created using only 17 and 24 volunteers respectively. Therefore, they may
not even reflect the general population, let alone the obese with their altered
body compartment sizes and (probably) altered equilibration rates.
Some consultants do use propofol/remifentanil anaesthetics for the obese,
and do it well. You do then get into a debate about which weight to use –
actual, lean or ideal. I don’t do it myself, but I gather that the trick is to use a
target somewhere between the ideal and actual body weights for the Marsh
model, or use the maximum weight that the pump will let you put in. HM
recently went to a SOBA (Society of Bariatric Anaesthetists) conference. They
were dismissive of this – too much guesswork based on too little evidence.
And all this in the presence of a tried and tested alternative – Desflurane and
Remifentanil.
3.4 What effect does the remifentanil have on the amount of
Desflurane that you are going to give this lady?
Just as there is a pharmacokinetic interaction between remifentanil and
propofol, there is a profound MAC-sparing effect of remifentanil on the
inhaled agents. This is true for all inhaled agents, but in practice, I would only
use desflurane. Why would you use an agent with a far prolonged wake-up
time when you have already gone out of your way to use remifentanil with
such a short and reliable wake-up time? Also, the patients you are likely to use
this technique on are likely to be intubated, ventilated and possibly paralysed
anyway.
Surprisingly, studies in this area are few, pretty badly thought out (in my
humble opinion!) and do not really help our understanding. In one study they
used 60% nitrous oxide in a desflurane/remifentanil anaesthetic. Why?

Anyway, there is a seemingly good study that shows the following;
Remifentanil
µg.kg -1 .min -1
(Estimated)
Remifentanil effect
site concentration
ng.ml -1
%age MAC
sparing of
desflurane
0.1 2.6 74 1.5
0.15 83 1
0.25 6.3 90 0.6
(Rough)
EtDes
(assuming
MAC=6.0)
So you could give her loads of remifentanil (and I would use 8 ng.ml -1 if
tolerated) and run the desflurane very low indeed (EtDes=1.0). I would never
run it that low, but you get the idea; an EtDes of 3.0 would be generous and
the patient would be very likely be asleep.
Also, this paper doesn’t quite agree with the nitrous paper I have just slagged
off. They should have been able to get the MAC even lower by using 60%
nitrous, but actually only showed a reduction to ET Des of 2.7% with 1 ng.ml -1
and 2.0% with 3 ng.ml -1 . So I feel justified at running the desflurane above 3%
with a higher infusion rate of remifentanil than they used.
3.5 What would be a sensible level for the remifentanil
infusion in this case; firstly at induction, secondly for
intubation, and thirdly for the initial abdominal surgery?
My opening gambit would be to start the remifentanil at a low dose whilst
checking drugs, equipment, and giving the antibiotics. A safe level would be 1
ng.ml -1 . Then, when it is time to start, induce with propofol and when you get
loss of consciousness, paralyse, up the remifentanil to 8 ng.ml -1 and start to
wash in some desflurane. Once you’ve allowed your relaxant to work, you can
obtund the stimulation of intubation by upping the remifentanil again to 10-12
ng.ml -1 . Then you can lower the target to 8 ng.ml -1 for surgery.
You want to avoid giving so much remifentanil that they stop breathing before
they are anaesthetised.

3.6 The case proceeds. The surgeons now want a double
lumen tube so that they can access the right hemi thorax.
What change in strategy might be useful here?
There is going to be extensive airway manipulation, which can be very
stimulating. In addition, you will not be giving any volatile for a while whilst
changing the airway. This actually isn’t too much of an issue; desflurane is not
broken down, and the body levels will not fall if you are not ventilating it out
of her.
It would be a good idea to up the remifentanil infusion at this point to a level
that would be compatible with an obtunded response to intubation; say 8 – 12
ng.ml -1 .
3.7 You wake the lady up and she is in pain; the epidural was
not all that you had hoped. What are we going to do?
Your remifentanil is still connected, so whilst you are either setting up for
another epidural or loading with morphine (remember; morphine takes a long
time to be effective –Munoz et al) you can run the remifentanil infusion. She
will still be a place of safety such as theatre, PACU or HDU/ICU, but you still
don’t want her to stop breathing on you whilst you are scrubbed up for the
epidural. A sensible level for post-op analgesia in the awake patient will be
0.05-0.15 µg.kg -1 .min -1 or a target of 1 ng.ml -1 .
4 Another case…
I did intend to write here about the type of ‘hybrid’ TIVA – a propofol infusion
with intermittent boluses of an opioid such as fentanyl. To be honest, I have
not heard of many people using this technique, and have not had a great deal
of success with it myself. This may be partly due to my familiarity with the
lower target propofol levels that I would use when running remifentanil
alongside; and remifentanil is much more forgiving than fentanyl.
If you were to try this technique, the mean levels required for loss of
consciousness are 5-6 µg.ml -1 , and if you have given some opioid, 4-5 µg.ml -1 .
Maintenance should be run at least 4 µg.ml -1 (Ce50 = 4.1 µg.ml -1 when
propofol run alone) and in my experience, much higher – usually around 6
µg.ml -1 . This will drink propofol quite rapidly…

5 The Full Monty: A gynae laparoscopy
You see a 27 year old lady on the morning of her surgery. She is listed for a
laparoscopy. She tells you that she’s otherwise well but that she “always
pukes” postoperatively.
5.1 Why TIVA?
She’s young and fit and has a high risk of PONV. This is unpleasant for the
patient and if it’s really bad, she may have to stay in hospital overnight which
she won’t enjoy and which is very expensive for the Trust. Remifentanil will be
gone before she gets out of the recovery room and propofol has its own,
intrinsic, anti-emetic properties.
5.2 Where do I start?
In the anaesthetic room, establish AAGBI monitoring and insert a freerunning
drip (some people insist on being able to see the drip during surgery
and/or inserting two drips so that you have a back-up if needs be. Instead, I
ensure that there’s a sevoflurane vaporizer on the back bar).
The patient weighs 70kg and has a BMI of 26 (not significantly obese) and
you’ve made your remifentanil up to 50 µg.ml -1 i.e. 2mg in 40ml NaCl 0.9%.
The remifentanil dose calculator tells you that to give her 0.5 µg.kg -1 .min -1 you
should run an infusion at 42 ml.hr -1 and give her an induction bolus of 1.4ml.
You start the infusion at 42ml an hour and give her a 1.4ml bolus. This has the
effect of brining her heart rate down to 75 from 100bpm and she tells you that
she’s feeling nice and light-headed. While you were waiting for this, you were
inputting her data into the propofol TCI pump. After appropriate preoxygenation
you induce anaesthesia by starting the propofol TCI at 8 µg.ml -1
(target plasma concentration). You note that the patient looses consciousness
at an effect site concentration of 1.0 µg.ml -1 . Ten seconds or so after loss of
verbal communication you reduce the propofol target to 4 µg.ml -1 and give
another 1.4ml bolus of remifentanil. Twenty seconds or so after this has
finished, you intubate the patient under good conditions with no coughing and
then reduce the propofol target to 2.2 and the remifentanil to 0.25 µg.kg -1 .min -
1 . Because you didn’t ventilate the patient between induction and intubation,
she doesn’t have any air in her stomach that would have increased her
incidence of PONV.
Intra-operatively she becomes slightly tachycardic (80bpm) and hypertensive
(120/80mmHg). You increase the propofol to 2.4 µg.ml -1 and the remifentanil
to 0.35 µg.kg -1 .min -1 and her heart rate settles to 60bpm but her blood
pressure sags to 65 mmHg systolic. You could reduce the propofol again but
for the extra peace of mind you decide to leave the infusion where it is and
treat with a mixture of permissive hypotension and occasional metaraminol
boluses.

At the end of the procedure, you feel that she is unlikely to have any significant
post-operative pain so you just give her a dose of IV NSAID. You turn off the
propofol five minutes before extubation and the remifentanil two minutes
before. This means that (in theory anyway!) the patient should still have some
remifentanil onboard as you extubate. You leave the ventilator on but remain
vigilant. The patient will open their eyes without any warning and in one fluid
movement, you will turn off the ventilator, deflate the ETT cuff and extubate,
all the while congratulating the patient on how well they’ve done and
reassuring them that everything went according to plan. No coughing or
gagging on the tube, just a patient who will be able to thank the theatre staff as
they are wheeled out to recovery.
5.3 When is this rapid wake-up advantageous?
The rapidity of the wake-up really is extraordinary. None of the five minutes of
coughing and bucking that you get with isoflurane et al; just a single cough (if
that). This is of real use for patients where coughing is a problem. For example
following open eye surgery or neurosurgery, coughing will raise the
intraocular pressure or intracranial pressure respectively, and could cause
problems with the surgical field. TIVA is also good for these patients as there
is reduced vomiting, which would have the same effect as coughing.
5.4 What are the pitfalls of this technique?
• Apnoea due to the remifentanil before you even start is a possibility but
they will breathe if you remind them to. This is especially true in
recovery and it’s important to tell the staff that they may have to
remind the patient for five minutes or so.
• Getting enough remifentanil onboard is key to intubating without a
relaxant. If you have poor view, closed cords or a significant
cardiovascular response to laryngoscopy, wait a little longer and give
another little bolus.
• Chest wall rigidity is reported if the remifentanil bolus is given too
quickly. I haven’t seen this.
• The window for intubation after a remifentanil bolus is sooner and
shorter than with suxamethonium. If you need two goes to get a good
look, you’re probably going to need another bolus.
• Overdose or underdose. As will all anaesthetic drugs, there is huge
variation and you do need to engage your brain. If the patient is frail or
cardiovascularly compromised, start the remifentanil at 0.25 µg.kg -
1 .min -1 and start the propofol at 0.2 mg.ml -1 and see how you go. Very
broadly speaking, the propofol will control blood pressure and
remifentanil will control heart rate. If you’re underdosing without
giving relaxant, you’ll know because the patient will move. We do not

ecommend TIVA with relaxant unless you have a depth of anaesthesia
monitor, especially at first until you find your feet.
• Hypotension is a common problem. You can give yourself grey hairs
trying to wean the propofol down without having the patient aware or
you can buy shares in metaraminol.
• Hyperalgesia. Again, although this is in every textbook, FS has never
seen it. If the patient is expected to be in pain postoperatively, we give
10mg morphine as a bolus approximately 10 minutes before the end of
the case (Munoz says it should be given 40 minutes before the end and
we intend to change our practice).
• PONV this can happen and is usually associated with the post-operative
analgesia rather than the anaesthetic. We suggest that opioid sparing
techniques are a good idea and that weak opioids tend to be weak
analgesics. Fentanyl in 25 µg boluses in the recovery room tends to
cause less nausea and vomiting than morphine. We give three or four
anti-emetics intra-operatively in these patients.

5.5 Another, different way of achieving induction
• Start your remifentanil at 1 ng.ml -1
• Get all your other drugs ready, check your ODP is in the anaesthetic
room, chat inanely with the patient, etc
• Start your propofol at a target of 4 µg.ml -1 , give the patient some
oxygen.
• Watch the Ce on the propofol pump. Note the level at which the patient
stops talking (usually around 1.8 – 2.2). You now know that with not
much remifentanil running, the patient is asleep at that Ce. At present
they do not have any stimulation.
• Turn up your remifentanil high – as tolerated by the patient in front of
you. Young, fit, well – maybe 10 ng.ml -1 or higher
• When the Cp of remifentanil is at that level and the Ce is climbing to
around the 10 ng.ml -1 mark, intubate without relaxant.
• Now turn down the remifentanil to your maintenance level (8 ng.ml -1 )
and the propofol to around 0.5-1 µg.ml -1 above the Ce you noticed that
they fell asleep st ( usually around 3 µg.ml -1 )
• The result is that you have a propofol level that you know is well above
that needed to keep them asleep. That was to no stimulus and with only
a little remifentanil running. Now you have loads of remifentanil
running. These levels of maintenance are supported by the literature
(Vuyk et al). The fastest wake-up times whilst ensuring 95% adequate
anaesthesia are around propofol 2.8 µg.ml -1 , remifentanil 7.6 ng.ml -1 .

Fortune favours the brave… TIVA for the connoisseur
This part is more for your general information. These considerations do not
apply to the syringe drivers currently available at Airedale.
5.6 Marsh vs Schnider – whats its all about?
Nearly all TCI syringe drivers will have the Marsh model for propofol
pharmacokinetic modelling. Some may, in addition, also have the Schnider
model. Why would you need two and what are the differences?
Both models are trying to mathematically describe what happens when
propofol is given, but they go about it in different ways and particularly when
the infusion is started. Eventually, by about 10 minutes, plasma level
estimated will be very similar. Overall, the Schnider model will lead to a
smaller total dose of propofol being given.
Not to bore you too much with pharmacokinetics, but the Schnider model has
a fixed and much smaller central compartment of 4.27 litres. The Marsh may
have a volume of around 16 litres which will vary with body weight. This will
mean that the initial boluses given at the start of the anaesthetic will be
smaller with the Schnider model if you are setting the same target that you
would do for the Marsh. Therefore, you will have to be patient; your machine
will be telling you that your Cp has been reached, but your eyes will tell you
that not much propofol has been given, as will the patient (who will probably
still be awake). So, this model is useful for those who you may want a slower
induction and lower dose of propofol – the elderly. This is where my (HM)
experience starts and ends with the Schnider model, and to be honest I have
recently moved to using VIMA (volatile induction and maintenance of
anaesthesia) for elderly, crumbly patients. But that is a whole other story…
The differences caused by this low central compartment volume model will
also be apparent on completion of the surgery. When you turn off your pump,
the calculated plasma level will fall very quickly. Knowing this is of little
practical value, but you will see it. There are other differences between the two
models; the rate constants for the movement of propofol between the
compoartments are slightly different. However, practically speaking, the main
difference is the size of the central compartemt.
All the cases in this workbook have been based on our experiences with the
Marsh model. Were you to start using the Schnider, exercise caution.

5.7 Target controlled infusions – blood or effect site
targeting?
If you are lucky, you may have advanced TIVA/TCI pumps that give the option
to choose between blood and effect site targeting. Put simply, they are one
pharmacokinetic step removed from each other; there is another rate constant
that describes the movement of propofol from the central to the effect site -
the Keo. This is how the pumps will display the Ce. For the pumps that can use
this for targeting, this is also what they infuse to – they will give the most
rapid boluses and calculated infusion to give that effect site concentration with
no overshoot. Practically, this means that any deliberate ‘overpressure’ that
you might want to do with plasma targeting to rapidly raise the plasma levels
is not needed. However, it may also mean that the initial bolus and infusion is
given very rapidly; something that not all patients will cope with. I am much
more of a fan the gently-gently approach to TIVA, and so don’t really like this
aspect.
Specifically, as alluded to earlier, it is becoming more clear that there is little
to be gained by using effect site targeting for Remifentanil. To achieve rapid
effect site rises, the plasma levels have massive peaks – to get an Ce of 6ng/ml
you may get a peak plasma level of 17 ng/ml and this could have severe side
effects such as bradycardia and chest wall rigidity. Besides, I not sure you are
gaining much – the equilibration between plasma and effect site for
Remifentanil is complete within 5 minutes anyway.
All cases in the workbook have been based on our experience with blood level
targeting for propofol and remifentanil.

The super-condensed, Airedale only, beginners guide
to TIVA
If the prior discussions have left you cold or very nervous, you probably
should not try TIVA without someone who knows what they are doing in the
building. And always have a plan B; most likely bailing out to an inhalational
technique. The following is a summary of the guide to minimise the number of
options, and give a newbee a better entry point.
So, to make things easier, only use the Alaris PK pumps, and only run
them on the plasma level target controlled infusion for both propofol
and remifentanil. The pumps will display the other units, but when you are a
beginner, only look at the Cp (plasma concentration) and the Ce (effect site
concentration).
I will go through three cases again using these pumps only, and slightly
simplified; low dose propofol for sedation for a patient undergoing spinal
anaesthesia, desflurane and remifentanil for the obese patient, and then a
combined propofol/remifentanil anaesthetic.
Conscious sedation during spinal anaesthesia
The patient is an 85 year old male, past medical history of hypertension and
gout, who presents for a TURP. You persuade him to have a spinal
anaesthetic, but he requests sedation during the procedure.
You remember seeing someone use a blood targeted propofol infusion for just
such an operation in the past, and think that you will attempt the same.
What are the three main advantages of propofol TCI over the
alternative drug, midazolam?
• Titratability
• Steep dose response curve for both drugs but propofol wears off more
rapidly
• Clear and rapid recovery of full consciousness
Midazolam takes ages to work, by which time you’ve given some more. Then
the two doses together are too much and the patient is anaesthetised. There is
also the usual interpersonal and age related variation in sensitivity to both
these drugs. At least with propofol it doesn’t last as long, and you have the
reassurance of an estimated plasma level for that patient based on their age
and weight.
Propofol TCI is a good technique for this sort of anaesthetic; there are no
analgesic requirements intraoperatively or postoperatively, so no need for
other drugs that may interact and lead to inadvertent unconsciousness.

What would be a sensible level for your infusion?
The usual dose range is between 0.5 and 1 µg.ml -1 . That said, your patients
may be old and sensitive, and remember that they’ll often fall asleep with just
the spinal in. I have had an 85 year old on the table who was difficult to rouse
on a plasma level of 0.5 µg.ml -1 , and he eventually ended up being comfortable
and rouseable on a target of 0.1 µg.ml -1 .
An oesophagectomy in an obese lady
You are presented with a 55 year old lady for an elective laparoscopically
assisted oesophagectomy for adenocarcinoma. She has an HDU bed booked
for her post-op recovery, and the consultant has talked to her about having a
thoracic epidural prior to induction. She is a little on the obese side, with a
BMI of 40.
The epidural is duly accomplished, and the anaesthetic is started. A
remifentanil infusion is started, the patient is induced using a propofol bolus,
and the consultant intubates with a single lumen tube. He then turns on the
desflurane.
What are the advantages of using remifentanil in this case?
For this case, an epidural has been sited for post-op pain relief, but the surgery
itself will involve stimulation at sites not covered by the block (airway, lower
abdomen). Also, you might not want to bolus your epidural at the start of
surgery so that you can avoid the haemodynamic effects just before the
pneumoperitoneum and changes in patient position. Remifentanil is ideal as
all areas will be covered intra-operatively, and when the remifentanil is turned
off on completion, the epidural will provide the analgesia in the area of postop
pain. The lack of systemic opiates still knocking around the bloodstream is
of advantage to this patient post-operatively; respiratory complications due to
under-breathing because of opiates or inadequately controlled pain are a
major cause of morbidity in these patients. As she is also obese, this will
further compound these issues and would make using remifentanil even more
advantageous.
You put the patient’s height and weight into your remifentanil TCI
pump, and it will not let you enter those figures. It lets you enter
the height, but then will not allow you to go up to the weight that
you want to enter. What are we going to do?
See the full text for an explanation; basically run the model with that
maximum weight it has let you put in. The levels in the patient will not be as
high as you think they are, so you will have to up your targets a bit.
Why has the consultant decided to use a volatile anaesthetic rather
than propofol TCI?
The propofol models are not designed for the obese. Therefore don’t use them.

What effect does the remifentanil have on the amount of
desflurane that you are going to give this lady?
Just as there is a pharmacokinetic interaction between remifentanil and
propofol, there is a profound MAC-sparing effect of remifentanil on the
inhaled agents. If you give her loads of remifentanil (and I would use 8 ng.ml -1
if tolerated – see below), you could run with the EtDes at 4.0.
What would be a sensible level for the remifentanil infusion in this
case; firstly at induction, secondly for intubation, and thirdly for
the initial abdominal surgery?
My opening gambit would be to start the remifentanil at a low dose whilst
checking drugs, equipment, and giving the antibiotics. A safe level would be 1
ng.ml -1 . Then, when it is time to start, induce with propofol and when you get
loss of consciousness, paralyse, up the remifentanil to 8 ng.ml -1 and start to
wash in some desflurane. Once you’ve allowed your relaxant to work, you can
obtund the stimulation of intubation by upping the remifentanil again to 10-12
ng.ml -1 . Then you can lower the target to 8 ng.ml -1 for surgery.
You want to avoid giving so much remifentanil that they stop breathing before
they are anaesthetised.
Remifentanil can cause bradycardia. If the patient becomes unduly
bradycardic, turn off the infusion to allow the plasma levels to fall and manage
appropriately; glycopyrolate / atropine… Then remember to turn the
remifentanil back on again, with a lower target.
The Full Monty: A gynae laparoscopy
You see a 27 year old lady on the morning of her surgery. She is listed for a
laparoscopy. She tells you that she’s otherwise well but that she “always
pukes” postoperatively.
Where do I start?
In the anaesthetic room, establish AAGBI monitoring. Programme the syringe
drivers – see the safety warnings earlier in the booklet.
Start your remifentanil at 1 ng.ml -1
Get all your other drugs ready, check your ODP is in the anaesthetic room,
chat inanely with the patient, etc
Start your propofol at a target of 4 µg.ml -1 , give the patient some oxygen.
Watch the Ce on the propofol pump. Note the level at which the patient stops
talking (usually around 1.8 – 2.2). You now know that with not much
remifentanil running, the patient is asleep at that Ce. At present they do not
have any stimulation.
Turn up your remifentanil high – as tolerated by the patient in front of you.
Young, fit, well – maybe 10 ng.ml -1 or higher

When the Cp of remifentanil is at that level and the Ce is climbing to around
the 10 ng.ml -1 mark, intubate without relaxant. You could go a little lower if
using a relaxant.
Now turn down the remifentanil to your maintenance level (8 ng.ml -1 ) and the
propofol to around 0.5-1 µg.ml -1 above the Ce you noticed that they fell asleep
at (usually around 3 µg.ml -1 )
The result is that you have a propofol level that you know is well above that
needed to keep them asleep. That was to no stimulus and with only a little
remifentanil running. Now you have loads of remifentanil running. These
levels of maintenance are supported by the literature (Vuyk et al). The fastest
wake-up times whilst ensuring adequate anaesthesia in 95% of patients are
around propofol 2.8 µg.ml -1 , remifentanil 7.6 ng.ml -1 .
What are the pitfalls of this technique?
Apnoea due to the remifentanil before you even start is a possibility but they
will breathe if you remind them to. This is especially true in recovery and it’s
important to tell the staff that they may have to remind the patient for five
minutes or so.
Getting enough remifentanil onboard is key to intubating without a relaxant.
If you have poor view, closed cords or a significant cardiovascular response to
laryngoscopy, wait a little longer and give another little bolus.
The window for intubation after a remifentanil bolus is sooner and shorter
than with suxamethonium. If you need two goes to get a good look, you’re
probably going to need another bolus.
Overdose or underdose. As will all anaesthetic drugs, there is huge variation
and you do need to engage your brain. If the patient is frail or cardiovascularly
compromised, start the remifentanil at a lower rate than detailed above and
see how you go.
Very broadly speaking, the propofol will control blood pressure and
remifentanil will control heart rate. If you’re underdosing without giving
relaxant, you’ll know because the patient will move. We do not recommend
TIVA with relaxant unless you have a depth of anaesthesia monitor, especially
at first until you find your feet.
Hypotension is a common problem. You can give yourself grey hairs trying to
wean the propofol down without having the patient aware or you can give
metaraminol/ephidrine.

Summing up
We hope that you’ve enjoyed reading this booklet and that it will be a useful
aide-memoire. We believe that TIVA is a very useful anaesthetic modality but
that it is not usually well taught. We have endeavoured to redress this but
would very much appreciate your feedback and/or constructive criticism to
frank.swinton@anhst.nhs.uk
Models to play with
There are a number of computer models that can help with understanding
what its all about. There are some others that are very difficult to use. These
are supposedly easier. I’m particularly hopeful about the iPad one…
Tivatrainer - we hope to get this on one of the computers at Airedale
Anesth assist PK/PD (for iPhone / iPad) - about £15, looks good, not tried it yet
Rugloop - free, not tried it yet, Windows only
References
• Albertin, Dedola, Bergonzi, Lombardo, Fusco, Torri. The effect of
adding two target-controlled concentrations (1-3 ng.ml-1) of
remifentanil on MAC BAR of desflurane. Eur J Anaesthesiol. 2006
Jun;23(6):510-6.
• Baerdemaeker, Mortier, Struys. Pharmacokinetics in obese patients.
Contin Educ Anaesth Crit Care Pain (2004) 4 (5): 152-155.
• Munoz, Guerrero, Brandes and Cortinez. Effect of timing of morphine
administration during remifentanil‐based anaesthesia on early
recovery from anaesthesia and postoperative pain. Br. J. Anaesth.
(2002) 88 (6): 814-818.
• Höhener, Blumenthal, Borgeat. Sedation and regional anaesthesia in
the adult patient Br. J. Anaesth. (2008) 100 (1): 8-16.
• Lesser. Remifentanil infusion calculation made simple. Anaesthesia.
2003;58:1035-6
• Mathews, Gaba, Zaku, Neuman.Can remifentanil replace nitrous oxide
during anesthesia for ambulatory orthopedic surgery with desflurane
and fentanyl? Anesth Analg. 2008 Jan;106(1):101-8.

• Nicholson, Hall. Diabetes and adult surgical inpatients. Contin Educ
Anaesth Crit Care Pain (2011) 11(6): 234-238
• Nöst, Thiel-Ritter, Scholz, Hempelmann, Müller. Balanced anesthesia
with remifentanil and desflurane: clinical considerations for dose
adjustment in adults. J Opioid Manag. 2008 Sep-Oct; 4(5): 305-9.
• Roberts, et.al. Induction and maintenance of propofol anaesthesia. A
manual infusion scheme. Anaesthesia 1988;43 Suppl:14-17
• Shine. Climate Effect of Inhaled Anaesthetics. British Journal of
Anaesthesia 2010; 105 (6): 731–3