Pediatric Anesthesia 2004 14: 374379
Update on TIVA
ROB EYRES FANZCA FRCA
Royal Childrens Hospital, Parkville, Victoria, Australia
Keywords: anesthesia; total intravenous; delivery systems; drugs;
propofol; remifentanil
Introduction
Mehernoor Watcha, over 10 years ago, wrote an
article for Current Opinion entitled Intravenous
anaesthesia for paediatric patients (1). The main
focus of the article was on the agents suitable for
intravenous (i.v.) anesthesia and in 10 years only
one new drug has been added to the list, remifent-
anil. Propofol, the main feature of Watchas paper,
still is not indicated for use in children <3 years old.
It is difficult from the literature alone to assess the
frequency of use of total intravenous anesthesia
(TIVA) in pediatric anesthetic practice, but as a pure
technique, it does not appear to be mainstream. In its
simplest form and without elaborate delivery sys-
tems, all that is required is a syringe, a needle,
respiratory management and monitoring, and this is
widespread practice in simple short cases. With the
introduction of more elaborate delivery systems
such as the Diprafusor and Paedfusor and a deeper
understanding of the pharmacological principles of
the drugs used, the popularity of TIVA has
advanced. Although i.v. anesthesia can be delivered
by bolus, single or multiple, a continuous variable
rate i.v. drug delivery system has advantages,
among which include:
greater hemodynamic stability;
more stable depth of anesthesia;
more predictable and rapid recovery;
Speaker: Rob Eyres, MD, Professor of Anaesthesiology, Director of
Anaesthesia and Pain Management, Royal Childrens Hospital,
Melbourne, Australia.
Correspondence to: Dr Rob Eyres, Director of Anaesthesia and Pain
Management, Royal Childrens Hospital, Parkville, Victoria,
Australia (email: rob.eyres@rch.org.au).
374
potential lower total dose of drug used;
less pollution and toxicity than incurred by vola-
tile agents.
Infusion devices
The simplest example of a continuous i.v. infusion
is represented by a simple syringe pump pro-
grammed at a set rate by the anesthetist and most
commonly used for muscle relaxants, propofol or
remifentanil in current clinical practice. These sim-
ple manual regimes controlled by the anesthetist
(manual controlled infusion: as opposed to target
controlled infusion, TCI) where anesthetists are
consciously making use of disposition kinetics well
tried, such as the 10-8-6 rule in adults. If the
pharmacokinetic parameters of a drug have been
described in detail then computer programs can
provide accurate and rapid calculations to make
automatic drug delivery systems independent of
human intervention. Automated delivery systems
can be classified as open loop control or closed loop
control systems. Open loop control system is where
the input to the system (in this case the amount of
drug delivered to the patient) is independent of the
output, i.e. there is no measurable feedback signal.
However, the set point of the drug concentration is
decided by the anesthetist. This system is also
known as a model-based control and is represented
by the commercially available Diprafusor. Closed
loop system is where at any given moment the
input to the system (i.e. the drug delivery) is a
function of the previous output (e.g. evoked poten-
tial, bispected index (BIS), blood pressure, pulse
rate). Here, there is a measurable feedback signal
which completes the loop.
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Open loop control systems
The Diprafusor is a TCI device for the adminis-
tration of propofol in adults introduced in late
1996 into over 100 countries except for the USA
where the Food and Drug Administration cannot
decide whether the system should be regulated as
a device or a drug. This TCI device allows the
anesthetist to administer propofol to a selected
target plasma or an effect compartment concentra-
tion and to change this set point if signs of
inappropriate anesthetic depth are manifest. The
device delivers a BET format (B loading dose,
E terminal elimination, T transfer to periph-
eral compartment of the drug) and a complicated
algorithm that contains pharmacokinetic parame-
ters derived from a small group of patients and it
is impossible that the algorithm will match all
patients. The Diprafusor accuracy has been valid-
ated in trials comparing predicted plasma concen-
trations as set on the device with those actually
measured. Performance comparisons are made
using the following terms.
Medial performance error or bias (MDPE): this
term represents the direction (over or under
prediction) of the error.
The size of the above-mentioned error from the
predicted value is reflected in the term median
absolute performance error (MDAPE).
The term wobble measures the potential of the
infusion system to maintain a constant set point.
A number of studies have validated the perform-
ance of the Diprafusor. The Diprafusor is of course
not recommended for patients <16 years of age, and
for good reason as the pharmacokinetics differ
between adults and children. In short, children have
a large central volume of distribution, almost double
that of adults and a more rapid clearance of drugs
used in TIVA. Using published kinetic parameters for
children, Absalom et al. adapted the Diprafusor to
produce the Paedfusor (2). In a study using the
Paedfusor, they realized an MDPE (bias) of 4.1% that
was far less than that found in comparable situations
in adult studies using the Diprafusor TCI system (2).
This figure has to be put into the perspective that
when endtidal isoflurane or halothane is used to
estimate the arterial concentration, the bias is of the
order of 20%. Varveris and Morton studied 30
children aged 6 months to 16 years undergoing
 2004 Blackwell Publishing Ltd, Pediatric Anesthesia, 14, 374379
UPDATE ON TIVA 375
simple elective surgery and confirmed the ease of
use, clinical efficacy and the absence of adverse
effects when using the Paedfusor (3). Patients were
for insertion of LMATM, breathing spontaneously
with a target plasma propofol concentration of
8 lgml)1 which corresponded to a calculated effec-
tor site concentration of 4.29 (1.05) lgml)1. A
higher value was needed for insertion of the regional
block. The average total propofol dose was highest in
the youngest age group, i.e. 623 months where
35 mgkg)1h)1 was needed compared with 27 mgk-
g)1h)1 in the 140192-month-old group. Once again
this is a reflection of differing volumes of distribution
and clearance in the young.
Closed loop systems
This type of control is not available commercially,
but is the subject of clinical investigation in adults.
Leslie et al. investigating adults undergoing colon-
oscopy with propofol alone, concluded that BIS may
be a suitable control variable for closed loop control
of sedation with propofol (4). Morley et al. using BIS
as a target of control, compared TIVA (propofol/
alfentanil) and general anesthesia (isoflurane/ni-
trous oxide) in both closed loop or manually con-
trolled administration of the above anesthetic
regimes and concluded convenience aside, the
closed loop system showed no clinical advantage
over conventionally adjusted techniques of anes-
thetic administration. (5). Although the closed loop
systems are not state-of-the-art, the technology will
develop. To be clinical robust the systems need:
superior sensor technology;
artifact detection and elimination.
Most feedback systems use a specific drug as one
input and one specific signal as an output. In the
clinical setting, several drugs are given and several
physiological variables are measured and monit-
ored, and this is the gap that exists between closed
loop systems and current clinical practice.
Reliability of infusion devices
Infuser algorithms are based on population phar-
macokinetics which do not cover all individuals.
Anesthesia in general terms provides an ED-95 to a
population for a procedure and aims to maintain a
narrow therapeutic window to ensure adequate
376 R. EYRES
anesthesia that will result in a prompt recovery.
There is at the moment no reliable technique for
monitoring plasma concentrations of drugs used in
TIVA and an increased risk of awareness with TIVA,
especially with the concurrent use of muscle relax-
ants, has been cited as a possible drawback to its use.
Clinicians using techniques relying upon volatile
agents for anesthesia have the security of endtidal
agent monitoring. The uncertainty in estimating
depth in TIVA is exacerbated by the literature
reports of device or operator failure leading to
paralyzed awake patients. However, two studies,
one by Sandin et al. (6) and one by Nordstrom et al.
(7) tend to refute this suggestion. Both are prospect-
ive studies of 11 785 and 1000 patients, respectively,
both using muscle relaxant techniques. Using gen-
eral anesthesia and endtidal CO2 monitoring the
incidence of awareness was 0.18% compared with
0.2% in TIVA. That a technique using BIS or other
electroencephalogram derived monitoring such as
mid-latency auditory evoked potentials is able to
reduce the incidence of awareness is questionable as
the sensitivity of these instruments is not 100%.
Sandin et al. commented that from the results of his
study, it was suggested that 861 patients would need
to be monitored with an instrument of 100%
sensitivity to avoid one case of suffering from
awareness (6). Awareness in the pediatric popula-
tion may be more difficult to define and adult data
may not be relevant. No recent surveys have been
performed in children. The last large survey in
children in 1973 (8) reported an incidence of 5% but
this large percentage was not supported by two
smaller subsequent studies. Less is known about the
interpretation of awareness in children and factors
such as higher anesthetic requirements (9) may
increase the risk. Monitoring devices such as BIS
are yet to be calibrated accurately in children (10).
Context sensitive half time
Of the three phases of anesthesia (induction, main-
tenance and recovery), it is the last phase which is
often the most unpredictable. The concept of context
sensitive half time was first expounded by Hughes in
1992 (11). He expressed the opinion that the terminal
elimination half-life provides a description of a drug
for a one compartment model, but has little practical
value in describing multicompartment models seen
with infusions in clinical anesthesia. Hughes used a
simulator and following a BET type infusion lasting
1500 min calculated the time required for a 50%
decrease in the central compartment drug concen-
tration as a context sensitive half time in which
context refers to the duration of the infusion. This
simulation mimics an infusion during anesthesia, set
to maintain a constant central compartment drug
concentration. These simulations, unlike the classical
terminal elimination half-life, account for the influ-
ence of the distribution process being the net transfer
of the drug out of the plasma into the peripheral
compartments and the reverse process with a
decrease to the infusion rate. The clinical relevance
of the reduction in the central compartment concen-
tration will be drug dependent. An understanding of
the context sensitive half time rather than the elim-
ination half-life provides a guide for choice of drug
and an indication when to terminate the infusion.
Pollution issue
Lack of pollution has been cited as one of the
benefits of TIVA. Of all the volatile agents examined,
halothane was found to be mutagenic in certain
in vitro tests and metabolized to reactive intermedi-
ates that covalently bind to cellular macro molecules
(12) and nitrous oxide has been implicated in
interfering in vitamin B12 metabolism with evidence
of genuine risk in health workers (13). Nitrous oxide
is also a potent greenhouse gas and the medical
proportion of nitrogen oxide emission is a significant
amount of the global total (14). These issues may be
balanced by the fact that the breakdown of propofol
leads to the formation of phenol which is classified
as number 2 on a list ranking the environmental
damage on a scale of 03.
Drugs used for TIVA
Even volatile agents can be given intravenously with
great care but there are two drugs that can be used
as indices for TIVA: an hypnotic, propofol and the
opioid remifentanil.
Propofol
The pharmacokinetics of propofol are characterized
by rapid effect, rapid clearance and distribution into
 2004 Blackwell Publishing Ltd, Pediatric Anesthesia, 14, 374379

the peripheral tissues leading to a short context
sensitive half time. The dynamics are described by a
clear-headed emergence, rapid return of orientation
and decreased nausea and vomiting which makes
the drug suitable but not optimal for TIVA. Unlike
remifentanil its offset is largely due to redistribution.
Children have a large central compartment and a
higher clearance when compared with adults.
Recommended adult induction doses of 2
2.5 mgkg)1 are almost half that used in small
children. Children will need infusion rates 50
100% higher than adults to maintain any desired
propofol concentration during the first 30 min (15).
This is demonstrated well by McFarlan et al. (9). To
describe the decreasing exponential dosing in adults
during a propofol infusion the 10-8-6 rule was
applied in his study. To achieve the same target
concentration in children a 15-13-11-10-9 (where the
numerals represent mgkg)1 at given time intervals)
rule was applied to achieve equivalent plasma
concentrations. The termination of drug effect with
propofol is largely due to redistribution of the drug
away from the central compartment rather than
elimination of the drug from the body. Larger
induction doses and higher infusion rates in children
are necessary to maintain similar blood concentra-
tions to that of adults and implies that at the
termination of the infusion more drug remains in
the body for any given plasma concentration than in
adults. This also implies a more prolonged recovery
in children (Table 1) (9). The context sensitive half
time derived by McFarlan et al. (Fig. 1) confirmed this.
The marketed formulation of propofol has some
undesirable properties:
pain on injection;
serious allergic reaction;
supports rapid microbial growth.
Previous attempts at altering the solvent for
propofol have been complicated by adverse hemo-
dynamic effects or negative effects on propofol
pharmacokinetics and the resultant change in
profile. A modified cyclodextrin preparation has
Table 1
Comparison of context sensitive half time between adults and
children for propofol
Duration Adults
1h 6.7 min
2h 9.5 min
 2004 Blackwell Publishing Ltd, Pediatric Anesthesia, 14, 374379
UPDATE ON TIVA 377
Figure 1
Context sensitive half-time of propofol in children and adults.
From McFarlan et al. The use of propofol infusions in paediatric
anaesthesia: a pratical guide (9).
been in trials in an attempt to avoid the side-effects
without a change in drug kinetics and the results
have been favorable.
Of interest is the propofol infusion syndrome
originally described in critically ill children under-
going long-term (>48 h) propofol infusion at high
doses (>4 mgkg)1h)1). Several cases have also been
reported in adults, but it must be emphasized that
this condition is rare and is thought unlikely to be
seen in the anesthetic situation. Two reports might
be of interest to the anesthetist. The first report is an
18-month-old child with some features of propofol
infusion syndrome following 5 h of 6 mgkg)1h)1
infusion of propofol (16). Although the clinical
features were consistent with the propofol infusion
syndrome (lactate acidosis, myocardial failure, renal
failure and hypertriglyceridemia), no claim of prop-
ofol infusion syndrome was made and with sup-
portive care the child recovered. Secondly, a report
by Wolf et al. of a more typical case of a 2-year-old
child with features of propofol infusion syndrome
occurring after a 72 h period at 5 mgkg)1h)1 of
propofol (17). He attributed recovery to hemofiltra-
tion. Their case report describes the pathogenesis:
propofol affects fatty acid oxidation by indirectly
inhibiting the transport into mitochondria of long
chain fatty acids;
medium and short chain fatty acids continue to
penetrate the mitochondria by diffusion, but a
Children
secondary inhibition occurs at complex II of the
respiratory chain inhibiting their metabolism;
10.4 min the resultant lack of substrate and a build up of
19.6 min
fatty acids account for the clinical features.
378 R. EYRES
Context sensitive half
time (min)
Context Half time Potency Clearance (mlmin)1)
Remifentanil 10 23 30
120 23
Alfentanil 10 10 1.0
120 45
Vc represents the central compartment of distribution. t1/2 Keo represents the half time taken for
equilibration between plasma and biophase.
Remifentanil
Along with esmolol and to some extent mivacurium,
remifentanil introduces a new control of kinetics in
anesthetic pharmacology. Methyl ester hydrolysis
occurs by blood and tissue esterases to produce a
major metabolite virtually devoid of activity (1 in
300 to 1 in 1000 as potent). Because most of the
hydrolysis occurs in tissues, plasma butyryl chol-
insterase deficiency has little effect on metabolism of
remifentanil. This has been demonstrated by Davis
et al. in vitro using pseudocholinesterase deficiency
patient plasma (18). This has also been confirmed in
vivo by a single case report by Manullang et al. (19).
As a side issue, major site of metabolism of esmolol
is the red cells and coadministeration of the two
drugs has no interreactive effect. Protein binding
may influence the metabolism of remifentanil by
offering a protective effect.
Alfentanil has been described and used as a short
acting opioid so a comparison of the kinetic param-
eters is useful (Table 2). From Table 2 the following
points were made.
Potency ratio will vary according to the endpoint
used.
Rapid onset of analgesia is seen with both drugs
with a peak effect in 13 min (t 1/2 Keo).
Clearance of remifentanil was relatively independ-
ent of dose.
The potential for alfentanil to accumulate is
indicated by the context sensitive half time.
Many clinical studies have been performed with
remifentanil in pediatric anesthesia and some points
were made.
Remifentanil provides rapid onset, excellent tit-
ratability and rapid offset.
Remifentanil, as expected, provides poor postop-
erative analgesia.
Table 2
Pharmacological parameters
comparing remifentanil with
alfentanil
Vc t1/2 Keo (min)
41.2 (17.4) 0.153 1.3
9.01 (0.97) 0.152 1.1
A more rapid recovery compared with alfentanil.
Many studies preempted or used anticholinergics
to treat potential bradycardia or hypotension.
A more rapid clearance was experienced in the
very young (<2 months old) compared with older
children.
Measured context sensitive half-life was in close
agreement with modeled results.
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