Anric~.rthc.sia,1988, Volume 43 (Supplement).

pages 1 4 - 1 7

Induction and maintenance of propofol anaesthesia

A manual infusion scheme

F. L . ROBERTS, J. DIXON. G . T. R. LEWIS. R . M . TACKLEY AND

C. PRYS-ROBERTS

Summary
A siwiplc~.i ~ i a t i u a l lcontrolled
~~ infusion scheme f o r c.oniinuous udministrution of'propofol M'OS derived by siwiulation of LI conzpzrter
ulgorithni ciesi<qtiedt o iichieve u predetermined blood concentration of' propofid within 2 minutes and to maintain a cwnstutit
blood levi~lfiw thc durution of .surgery. The munual injiision ,scheme fhr a target blood propofol concentrotion of 3 pg,~nil,
,

c~on.sistcrlof'a louding dose of 1 mg/kg fbllowed itnnwdiately bjs uti infusion o j 10 nq/kg/liour,for I0 minutes, 8 mg/kg/lioitr,for
tlic nevt I 0 minirtcs und 6 tng/kg/liour therei$ter. An overall mean blood propof"l concentration o f 3.67 pglml ,$,as achieved
within 2 minutes m d mnintriined stable .for the subsequent 80 -90 mitiurrs of rurgerj.. The decrrase of' sysrolic and diastolic
P S intirrction W N S tnucli less thin tliat previousli. described iifier Itrrgcr induction doses of'propo/Cd mid r h r r r wus
iwtrr-id ~ ~ P . F . I L I ~(11
it negligihle liucmodynumic response to 1urg)~ngoscop~ and intubution or to the siibsequent surgery. The gua1it.v of induction and
niuintenancc of' cinaesthesia t i m .rati.sfiic.torj in ever.)' putirnt.

Key words
Anucsthr*fic:s.intr-uvrtrous; propofol
A n u e s f h r ~ t i ctechniques: infusion.

Propofol. by virtue of its favourable pharmacokinetic
profile, has already achieved considerable popularity for
induction and maintenance o f anaesthesia for short dura-
tion surgery. The same profile has ensured its suitability
for continuous infusion for prolonged surgery and also for
sedation in intensive care units. The infusion rates of pro-
pofol to supplement nitrous oxide anaesthesia required
to suppress movement in response to the initial surgical
stimulus have been determined in patients who have
received a variety o f prernedications. I - 3 The whole blood
concentrations required to achieve such anaesthetic states
were determined at the same time and were confirmed in
a series or haemodynamic and pharmacokinetic studies
during continuous infusions.4-6
Many strategies have been described to enable predeter-
mined blood levels of anaesthetic and other drugs to be
achieved. The simplest, a zero-order infusion. was used to
achieve sedation during regional anaesthesia and in order
to study the pharniacokinetics of propofol." The time taken
for thc blood propofol to reach a stable state exceeded an
hour.
A number of'complex infusion schcmes have been devised
based on the analyses of Wagner,' Vaughan and Tuckers
and others. of which the BET (bolus. elimination, transfer)
scheme ha5 been shown to be effective for other anaes-
thetics and analgesics."- I ' This scheme is based on the
following premises: a loading dose (bolus) is required to fill
the initial volume o f distribution of the drug; a final in-
fusion rate can be achieved which equates to the clearance
(elimination) of the drug; and an interim infusion scheme i s
necessary to match the redistribution (transfer) of the drug
from the central volume of distribution to more peripheral
sites.
,A computer controlled infusion system based on a thrcc-
compartment pharmacokinetic model. was designed to
achieve a whole blood propofol concentration of 3.0 &ml
within 5 minules and t o maintain it constant throughout
the period o f surgcry. This system was tested and shown to
achieve the desired blood Icvcls.' An tincxpccted bonus
was the finding that arterial pressure dcclined more slowly
than when a single loading dose of propofol 2.5 mg:'kg was
given intravenously. ,',I4 The same infusion program was
applied in a s u h q u e n t study to determine whether a pre-
induction diise of fentanyl 5 jigikg causes a pharmaco-
kinetic interaction w i t h propofo1.I The results of the latter
study confirmed the v;ilidity of the infusion model.
Most anaesthetists d o not have iicccss t o a micropro-
cesso I' con t 1 - 0 1ler o I- a cn in pu ter enabled v o I uinc t ric i n fu scr

F.L. Roberts, M B . ChB, FFARCS. J . Dixon, MB. BS, FFARCS, Senior Rcgisti-ars, G.T.R. Lewis. MSc. BTech, Senior
Medical Physicist. R . M . Tackley. BSc. MB. BS. FFARCS, Senior Registrar. <-. Prys-Roberts, DM, PhD. FFARC'S.
FFARACS. Professor, Sir Humphry Davy Department o f Anaesthesia. University of Rristol, Bristol Royal Infirmary.
Bristol RS2 8HW.

0003- 1409/88,'43S014 + 04 S03.00/0 (c) 1988 The Association o f Anaesthetists of Gt Britain and Ireland 14
 A manual infusion scheme 15

so wc sought to develop a scheme which allows an anaes-
thetist to control a standard infusion pump in such a way
as t o approximate the program used by the computer
controller. We present here the development and validation
of such it scheme adapted for the infusion of propofol.
Methods
Our initial scheme was based on thc parameters and
variables of thc equation which describes the three-
compartment model and which would predict a desired
whole blood propofol concentration (C,) of 3.0 pg/kg:
c', = Ae-zl + Be-/I' + C'e-;"
wher-e A . B and C are the y-axis intercepts and a, j and y
the exponential rate constants of the relationship. The
values of these parameters were derived from our own
data l 6 and those of Gepts and colleagues6 based on con-
tinuous infusion of propofol. Previous schemes based on
pharinacokinetic data derived from single dose sludies of
propofol '' underestimated the initial volume of distribu-
tion of the drug and resulted in the prediction of too low a
loading dose.
Figure I shows how a four-stage infusion scheme approxi-
mates the computer controlled infusion scheme. The
manual infusion scheme was as follows: loading dose 1
mg/kg over 20 seconds; 10 mglkg for 10 minutes; 8 mg/kg
for 10 minutes: and 6 mg/kg thereafter.
Ten patients aged between 25 and 64 years who presented
for superficial body surgery, who weighed 51- X7 kg and
were classed as ASA grade 1 or 2, were premedicated with
temuepam 2&30 mg 90 minutes before operation. A 16-
gauge cannula was placed in a forearm vein for infusion of
propofol from a 60-ml syringe in a Vickcrs Trconic 1P4
infusion pump. A second 16-gauge cannula was placed in
an antccubital vein in the contralateral arm for sampling of
blood.
Fentanyl 3 pg/kg was injected intravcnously 2 minutes
before the start of the infusion of propofol as described
above. Neuromuscular blockade was achievd with vecuro-
nium 0. I mgikg. The patients' trachcas were intubated and
ventilation was controlled subsequently with a Penlon--
Nuffield ventilator connected to a Bain system. Anaesthesia
was maintaincd with 67% nitrous oxide in oxygen; the fresh
gas flow was adjusted to maintain an end tidal carbon di-
oxide concentration of 5.0 kPa.
Venous blood was sampled at 2, 5, 10, 15, 20, 30, 40, 50,
60 and 80 minutes from the start of the infusion of propofol
and stored at 4°C until analysis by an HPLC method with
fluorometric detection. The electrocardiogram (CM5
Icad) was displayed continuously and arterial pressures
wcre measured immediately aftcr cach blood sample was
withdrawn and at intervening 5-minute intervals with a
Dinamap 845 automatic oscillotonomcter.
Results
All the patients studied lost consciousncss within one
minute after the loading dose and the first infusion, and
remaincd anacsthetised adequately throughout the surgical
procedurc. N o patient complained of pain in the arm
during administration of the loading dose.
The blood conccntrations of propofol are shown in
Table I. and thc mean values up lo the first 30 minutes of

100 r
got i

'OI
10
-I' 1.0 f

I 1 I I 1 1
0 5 10 15 20 25 30
Time (minutes)

Fig. I . Comparison of the decay of infusion rate as controllcd by a computer program (small incremental steps") with the thrcc-stage
manudly controlled infusion. and mean whole blood propofol concentrations measured at the appropriate times. Both infusion schemes
comnirnce after the injection of I mg:kg as a loading dose delivered over 15-20 seconds. The present scheme underestimates the correct
infusion rate in the first 5 minutes but overeslimates the correct ratc in thc subsequcnt 5 minutes. These underestimates and overestimates
are reflected in the blood concentrations. which are respectively lower and higher than the previous values.

Table 1. Whole blood propoibl concentrations a t various times from the start of infusion.
Time. minutes
2 5 10 15 20 30 40 50 60 80
___
Mean (SD) proporol
conccntration. pcg!ml 3.62(1.15) 3.24(0.83) 3.98(0.87) 3.62(0.74) 3.76(0.57) 3.39(0.55) 3.57(0.50) 3.86(0.57) 4.07(0.84) 3.79(1.04)
 16
160
2 140
10
I I
0 10 20 30
Time (minutes)
Fig. 2. Chiungt.9 o f systolic and diastolic arterial pressure (Innits of shadcd area) and heart rate during infusion of propofol
anaesthesia arc also shown in Fig. I . The mean value at
2 minutes was slightly higher than the target valuc and the
mcan values remained consistently higher than the pre-
dicted target 01' 3.0 pgjml throughout the infusion. N o
mean valuc from 5 minutes onwards differed significantly
from the mean value reachcd at 2 minutes.
Systolic and diastolic arterial pressures and heart rate
decreased slowly within the first 5 minutes (Fig. 2) but
remained stable thereafter throughout the infusion. There
were no significant changes of arterial pressures or heart
ratc i n response t o laryngoscopy and intubation.
Discussion
The main objective of thc present study was to develop and
validatc a simple scheme for manual control of a propofol
infusion to achieve a predetermined target concentration of
propofol in blood within 2 minutes and to maintain that
concentration constant for the duration o f the infusion.
This objective is important for a number of reasons, both
for the researcher and thc clinical anaesthetist. For the clini-
cal pharmacologist there is a great advantage in the rapid
attainment of a constant predetermined blood concentra-
tion of :any drug. The concept was originally proposed
by Kruger-Thiemer l 9 and subsequently by Mitenko and
Ogilvie'" and Wagncr.' The quest by anaesthetists came
late and w a s related to the development of intravenous
infusion anaesthesia.q- I z . z l - z 2 One of the difficulties when
drug requircinents for continuous infusions of intravenous
anaesthesia ;ire to be established, is that of achieving a
stable blood concentration of the anaesthetic within a fcw
minutes of the start of the infusion. With gases o r volatile
anaesthetics it is easy to measure thc alveolar (end tidal)
conccntration of the agcnt on a breath-by-breath basis and
adjust thc inspired concentration so as to maintain the
alveolar (and thus the blood) conccniration stablc. This is
n o t feasible with intravenous anaesthetics at prescnt so the
objective can be achicved only by an infusion scheme which
can be validated by retrospective measurements of the
blood concentration of the rclevant drug. This we have
donc for propofol using an open-loop computer control
system based on the established pharniacokinetic par-
ameters for the drug administered as a constant infu-
1 I I I
40 50 60 70 80
sion.6,'6 Given the weight of the patient. we can propose
an infusion schemc operated by a RRC-B micromputcr and
an IMED 929 computer enabled infusion pump which will
achieve any dcsired blood propofol concentration within 2
minutes and maintain that concentration reasonably const-
ant for the duration of anaesthesia.
The target blood concentration can be determined only
by studies which define the EC,, and EC,, for a given
intravenous anaesthetic under the conditions which are
proposed for a specific type of surgery. For instance, the
relevant values have been detcrmined for propofol infusions
to supplement 67% nitrous oxide anaesthesia in patients
premcdicated with lorazepam o r morphine.z.3 From these
and the empirical approaches used by many otbcrs. i t is
clear that ;I blood propofol concentration of about 3.0
pg/nil is adequate to maintain surgical anaesthesia when
combined with nitrous oxidc or alfentanil in a total intra-
venous technique.
The average clinical maesthetist does not have access 10
a computer controlled system such as that described above
and must therefore resort to manual control of appropriate
infusion schemes. A number of schemes have been devel-
oped on empirical clinical grounds and shown to provide
adequatc conditions for surgery but only one. a two-bottle
diltition system for ~mcthohcxitone.~~ was shown consist-
cntly to provide the requircd blood concentration.
Thc method dcscribed here overcomes most of the prob-
lems previously encountered and enables a stable blood
concentration to be achieved within 2 minutes of in.jection
of the loading dosc and the start of the infusion. The kin-
ctics of propofol arc linear within the range likely to be
required for continuous infusions l 6 so higher or lower
targct concentrations can be achieved by a proportional
increase of the four componcnts of the scheme. The varia-
tion between patients is similar to that obtained in previous
pharniacokinetic studies of propofol and represcnts the
inherent variation which inevitably occurs when population
kinetic statistics are applied for this purpose.'" 2 5 The rapid
attainment of the target level was achieved only after the
value for the initial volume of distribution of propofol was
modified according to the data derived from infusion
studies 6 , I rather than from single dose kinetic studies. '
The values for the initial volunie of distribution ( V i ) in the
 A munuul infusion scheme 17

latter study were 42.3 litres (SEM 5.9) in men a n d 36.1 preliminary report. Postgradua!e Medical Journal 1985; 61
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5 minutes. establishing steady-state drug concentrations using two con-
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O n e m a j o r a d v a n t a g e became a p p a r e n t d u r i n g the assess-
Pharmacology 1975; 9 235-8.
m e n t of t h e c o m p u t e r controlled infusion'* and d u r i n g t h c 9. SCHUTTLER J. SCHWILDEN H, STOECKEL H. Infusion strategies
present study: t h e decreases o f systolic ( - 30 m m H g ) a n d to investigate the pharmacokinetics and pharmacodynamics of
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t h a n t h e decreases (systolic pressure -46 m m H g , diastolic
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pressure ~ 12 m m H g ) observed t o follow a loading d o s e of cd. Qumiriraiiun, inodellinR and control in anaesthesia. Stutt-
2.0 ingikg in patients o f c o m p a r a b l e age.4 T h e decrease of gart: Georg Thieme Verlag, 1985: 260-8.
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Applications of pharmacokinetic concepts in clinical anaes-
after propofol 2.0 m g / k g were even greater i n an o l d e r
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after a n induction d o s e o f 2.0 m g i k g can b c cstiniated t o b e 2. TACKLLY RM. LEWISGTR. PRYS-ROBERTS C, BOADENRW,
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941P.
Phar-inaceuticals (UK) for their continued s u p p o r t o f t h e
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