Drugs 2007; 67 (5): 701-723

REVIEW ARTICLE 0012-6667/07/0005-0701/$49.95/0

© 2007 Adis Data Information BV. All rights reserved.

Induction of Anaesthesia
A Guide to Drug Choice
Nathalie Nathan and Isabelle Odin
Department of Anaesthesia and Intensive Care, CHU Dupuytren, Limoges, France

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
1. Cardiovascular Effects as the Main Factor in Drug Choice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
1.1 General Cardiovascular Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
1.2 Vasodilatation and Baroreflex Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
1.3 Cardiac Output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
2. Equipment and Anaesthetic Technique as a Factor in Drug Choice . . . . . . . . . . . . . . . . . . . . . . . . . . . 707
3. Choice of an Induction Agent for Upper Airway Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
3.1 Intubation Using Neuromuscular Blocking Agents (NMBs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
3.2 Intubation Without NMBs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709
3.3 Crash Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710
3.4 Laryngeal Mask Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
4. Patients with Increased Intracranial Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712
5. Patient Satisfaction and Quality of Awakening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713
6. Cost of Anaesthesia as a Criterion for Drug Choice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716

Abstract In developed countries, the choice of an anaesthetic agent for induction of

anaesthesia remains based mainly on its pharmacodynamic properties. Until now,
cardiovascular effects were the main factor in this decision. However, other
factors, such as the depth of anaesthesia and effects on cortisol synthesis, can
modify this simplistic view. A better understanding of the relationships between
the pharmacokinetics and pharmacodynamics of these drugs, and the availability
of new techniques, such as target-controlled infusions of anaesthetic drugs and
inhalation induction, have led practitioners to the understanding that the way a
drug is administered is a far more important factor for maintaining haemodynamic
stability than the specific agent used. The ability of a drug to maintain spontane-
ous ventilation and to relax the upper airway is another factor in this decision,
especially when considering difficult intubation, laryngeal mask insertion or
tracheal intubation without neuromuscular blockade. Beyond the factors men-
tioned above, anaesthetists adapt current practice to suit patients’ willingness to
comply with anaesthesia and to avoid the adverse effects that are most often
feared by the patient. Although most practitioners are not concerned with the cost
of anaesthesia, cost-containment policies have led some institutions to restrict the
use of the more expensive drugs to particular indications. However, this is too
simplistic an approach for the reduction of global costs, as other direct medical
costs, such as those for staffing, form a greater proportion of total costs than do
702
direct drug costs. Cost-benefit and cost-efficacy studies of the anaesthetics used
for induction of anaesthesia are needed to help anaesthetists to choose a drug
based on both cost and pharmacodynamic or pharmacokinetic properties.
For a long time, anaesthesia was induced using
intravenous thiopental sodium. In the late 1980s,
etomidate started to be used, followed by propofol;
the latter progressively replaced thiopental sodium
despite its higher cost.[1,2] The development of total
intravenous anaesthesia (TIVA) and target-con-
trolled infusions (TCI) of anaesthetic drugs in the
early 1990s, led to the concept of anaesthesia using a
single agent for both induction and maintenance,
eliminating the transition phase.[3,4] More recently,
in the late 1990s, sevoflurane was introduced into
the practice of anaesthesia, and has been used for
both induction and maintenance of anaesthesia,
bringing back into use the inhalation induction tech-
niques that were used prior to the introduction of
intravenous anaesthetics, especially for ambulatory
surgery.[5-7]
Many drugs, administered either intravenously or
by inhalation, may be used to induce anaesthesia.
The choice of drug for induction of anaesthesia is
mainly dependent on clinical endpoints, anaesthe-
sia-related morbidity and mortality being the most
important. The second factor that may influence the
choice of drug is the planned method of upper
airway control and whether spontaneous ventilation
has to be preserved. Minimising morbidity and up-
per airway control may be achieved by drug delivery
using special list equipment not available to all
anaesthetists, such as TCI systems, and equipment
for measuring the depth of anaesthesia. Pharmacoki-
netic considerations affect the choice of anaesthetic
in cases of rapid sequence induction or ambulatory
anaesthesia. Patient satisfaction, willingness to com-
ply with treatment and quality of life are also strong
criteria employed in deciding which drug should be
used, except if the patient choice of drug is at odds
with its safety or the need for rapid upper airway
control. Because of the number of anaesthetic proce-
dures performed daily, the clinician must consider
the cost of anaesthesia induction in view of cost-
© 2007 Adis Data Information BV. All rights reserved.
Nathan & Odin
containment policies. Finally, some drugs or tech-
niques can be definitively contraindicated.
This review compares the arguments for choos-
ing thiopental sodium, propofol, etomidate or
sevoflurane for induction of anaesthesia in adults. A
literature search was performed in the MEDLINE
electronic database, encompassing the period from
1980 to January 2007 without language restriction
and using the following terms: ‘thiopental’, ‘pro-
pofol’, ‘etomidate’, ‘ketamine’, ‘sevoflurane’, ‘an-
aesthesia and induction’, ‘intubation’, ‘laryngeal
mask’, ‘arterial pressure’, ‘haemodynamic’, ‘in-
tracranial pressure’, ‘cost’, ‘postoperative nausea’,
‘vomiting’, ‘awareness’, and ‘adverse effect’. After
reading the title and abstract, only articles in French,
German and English that were judged to be relevant
for the purpose of this review were obtained.
1. Cardiovascular Effects as the Main
Factor in Drug Choice
The analysis of cardiac arrest or death during the
induction of anaesthesia reveals that overdose or a
choice of drug that is unsuitable for the patient’s
cardiovascular status is the second most frequent
cause of anaesthesia-related death, with poor man-
agement of the cardiac arrest itself being the most
frequent cause.[8] Similarly, cardiovascular compli-
cations are one of the most common causes of
anaesthesia-related morbidity.[9] According to
Pedersen et al.,[10] cardiovascular events have an
incidence of one in every 170 anaesthetic proce-
dures, with a third of these being cardiovascular
collapse. A French regional epidemiological
study,[11] documented 11 peranaesthesia cardiac ar-
rests in 101 760 anaesthesia procedures, five of
which occurred during general anaesthesia and four
during induction of anaesthesia. Two of the events
that occurred during induction resulted from hypox-
aemia, and two from cardiovascular collapse or
asystole. Although numerous clinical reports sug-
Drugs 2007; 67 (5)
Drug Choice for Anaesthesia Induction 703

gest a direct role of inappropriate anaesthetic choice
in the occurrence of cardiac arrest or death in associ-
ation with anaesthesia,[12-16] no randomised study
has demonstrated that the choice of a specific agent
for induction of anaesthesia is associated with an
increased risk of cardiac arrest, death or cardiovas-
cular complications.[17] This excludes, of course,
cardiac arrests/death following malignant hyperther-
mia or death induced by acute immunoallergic hepa-
titis related to the use of a halogenated agent (ex-
cluding sevoflurane which has a metabolite that
does not induce this adverse reaction).
The haemodynamic consequences of the drugs
and techniques used for the induction of anaesthesia
have been fully investigated and numerous data are
available to help the clinician to make a rational
choice about which agent to use for induction. Even
if the typical cardiovascular effects of an anaesthetic
are described in most textbooks of anaesthesia, the
user must remain cautious about the theoretical anal-
ysis found in the literature. Indeed, the conse-
quences of an anaesthetic depend on how it is ad-
ministered, its pharmacokinetics, what opioids (and
their dosages) it is used in association with, and the
underlying cardiovascular status of the patient.
1.1 General Cardiovascular Effects
The cardiovascular effects of the drugs used for
induction of anaesthesia have already been de-
scribed in numerous articles and textbooks, and are
summarised in table I. This table is only indicative,
as in most cases these cardiovascular effects were
evaluated without an accurate measure of the depth
of anaesthesia, such as bispectral index monitoring,
which was previously unavailable. Moreover, prin-
ceps publications were either not comparative stud-
ies or compared the ‘new drug’ with an anaesthetic
that is no longer in use.
In clinical practice, the cardiovascular effects of
agents used for induction of anaesthesia are mea-
sured by variations in arterial pressure and heart
rate. In populations with specific cardiac risk fac-

Table I. Comparative effects of anaesthetics on cardiovascular parameters when used as the sole agent for induction of anaethesia (for
ketamine, see section 1.1)a
Cardiovascular parameter Isoflurane Desflurane Sevoflurane Thiopental Propofol Etomidate
sodium
Mean arterial pressure ↓ ↓b ↓c ↓20–30% ↓30% ↔
Heart rate
<1–1.5 MAC – Cp50 ↔ ↔ ↔ ↑ ↔↓ ↔
>1–1.5 MAC – Cp50 ↑ ↑ ↑ NA NA NA
Peripheral vascular resistance ↓↓ ↓ ↓↓ ↓ ↓↓ ↔
Myocardial contractility ↓ ↓ ↓ ↓↓ ↓↔ ↔d
Diastolic function ↓ ↓↓ ↓ ↓ ?
Baroreflex response ↓↓ ↓ ↓↓ ↓↓ ↓ ↔
Pacemaker excitability ↔ ↓e ↓e ↔ ↔
Myocardial excitability ↑ ↑ ↑ ↔ ↔ ↔
Atrioventricular conduction ↔ ↔ ↔ ↔ ↓f ↔
Intraventricular conduction – QT ↔↑ ↑ ↑ ↑ ↔ ↔
interval
a Comparative effects of intravenous anaesthetics and halogenated agents are given for equivalent potencies, in terms of the Cp50
and the MAC, respectively.
b During maintenance – dose dependently.
c During induction as the sole anaesthetic, dose-dependence and unknown mechanism.
d Dose-dependent cortisol synthesis blockade
e With junctional rhythm.
f With opioids.
Cp50 = concentration producing an effect in 50% of patients; MAC = minimum alveolar concentration; NA = not available; ↑ indicates
increase; ↓ indicates decrease; ↔ indicates no effect; double arrow indicates marked change; single arrow indicates moderate change.

© 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (5)
704
tors, the magnitude of these can favour the choice of
a drug with the least cardiovascular effect. A 30%
variation in arterial pressure or heart rate is the
threshold value used to ensure haemodynamic toler-
ance, although there is no scientific demonstration
of its pertinence.[18]
The decreases in arterial pressure of 20–30%
following administration of thiopental sodium result
from direct venous vasodilatation, reduced myocar-
dial contractility and a decreased baroreflex re-
sponse.[19-22] The reflex increase in heart rate follow-
ing thiopental sodium bolus injection may be attenu-
ated by opioids.[23]
The fall in arterial pressure observed with pro-
pofol is similar to that associated with thiopental
sodium, but results only from its venous vasodilato-
ry effects and from an alteration of the baroreflex
slope. Without opioids, the decrease in arterial pres-
sure can be partially compensated for by a reflex
tachycardia in patients whose basal sympathetic
tone is preserved. Usually, a decrease in heart rate is
observed due to the combination of this agent with
an opioid.[24-26] The haemodynamic consequences of
a propofol-opioid association depend on the dose[27]
and pharmacokinetics of the opioids. For example,
with remifentanil, which has a low blood-brain
transfer coefficient, the drop in arterial pressure may
be greater than with fentanyl and sufentanil.[28] In
elderly patients or those with cardiovascular disease,
the fall in arterial pressure associated with propofol
administration also depends on the rate of propofol
injection.[29]
In clinical practice, the effects of propofol and
thiopental sodium on heart rate and arterial pressure
during induction of anaesthesia are considered to be
similar.[30] Some minor differences in the cardiovas-
cular effects of these two anaesthetics have been
observed (see table I). Arterial pressure and heart
rate are often higher after administration of thiopen-
tal sodium than propofol, owing to the differential
effects of these drugs on the baroreflex response and
vasodilatation.[31-36] Differences in the duration of
deep anaesthesia after a bolus dose may also explain
this difference. Indeed, the depth of anaesthesia,
measured by the bispectral index, is less with thio-
© 2007 Adis Data Information BV. All rights reserved.
Nathan & Odin
pental sodium than propofol and is of shorter dura-
tion.[37]
On the other hand, administration of an etomidate
bolus is not associated with effects on arterial pres-
sure and heart rate.[24] Adding an opioid to treatment
does not modify this favourable cardiovascular tol-
erability in patients without hypovolaemia. Howev-
er, in hypovolaemic patients, etomidate use will not
impede the fall in arterial pressure and bradycardia
that is induced by opioids.[28]
Similar haemodynamic effects are usually ob-
served with sevoflurane inhalation and propofol ad-
ministered as intravenous boluses or TCI.[5,38-40]
Slight differences suggest better haemodynamic sta-
bility with sevoflurane. When arterial pressures are
the same, the heart rate is slower with sevoflurane
than propofol.[41] When mean arterial pressure is
higher with sevoflurane, then the heart rates are
similar for these two agents.[42] Jellish et al.[43] also
found that, in 186 American Society of Anesthesiol-
ogists (ASA) grade I or II patients, a greater
haemodynamic stability with sevoflurane adminis-
tered at concentrations that were progressively in-
creased by 0.5% steps than with 1.5–2 mg/kg pro-
pofol boluses. The same results were obtained by
others using 8% sevoflurane in nitrous oxide.[39]
The haemodynamic stability associated with
sevoflurane for induction of anaesthesia in younger
patients and those without specific cardiovascular
risk factors may indicate the value this agent could
have when used in elderly patients or those with
cardiovascular diseases. In hypertensive patients,
changes in cardiovascular parameters are similar
when intravenous propofol bolus and inhalation
techniques are used for induction of anaesthesia,
provided they are used without adjuvant opioids or
nitrous oxide.[44] However, high incidences of both
hypertension and reductions in arterial pressure are
observed in hypertensive patients, regardless of the
technique used for induction of anaesthesia:
sevoflurane or propofol, TCI or bolus, and with or
without opioids and/or nitrous oxide as an adju-
vant.[40,44,45] The magnitude of the risk of hypoten-
sion depends on the doses of the opioids used in
combination with the anaesthetics.[27,46] When in-
Drugs 2007; 67 (5)
Drug Choice for Anaesthesia Induction
duction of anaesthesia is performed without opioids,
a risk of hypertension is present, resulting from
either sympathetic activation or tracheal intuba-
tion.[45] With small opioid doses, the arterial pres-
sure and heart rate remain stable and induction of
anaesthesia is quicker compared with not using
opioids.[40,47] However, the so-called sympathetic
activation phenomenon is the main limitation to
sevoflurane use in patients at haemodynamic risk. In
two studies, a sharp increase in heart rate and, in
some cases, arterial pressure, characteristic of this
syndrome, were observed 2–3 minutes following
administration of high sevoflurane doses.[48,49] The
sympathetic activation phenomenon may be more
frequently observed in young patients whose
baroreflex response is preserved.[45] High end-tidal
sevoflurane concentrations may trigger this re-
sponse, which is observed in parallel with paroxys-
mal electroencephalographic epileptoid altera-
tions.[48,49]
Despite its apparent simplicity, to argue for the
use of a specific anaesthetic solely based on the
effects that it has on heart rate and arterial pressure
can lead to errors in treatment choice. Cardiovascu-
lar collapses with asystole has been observed in
elderly patients receiving propofol at too fast an
injection rate and at too high a dosage.[50-52] Cardiac
arrests have also been described during induction
with inhaled sevoflurane, due to either drug over-
dose or its use in combination with opioids, even
when using moderate doses of opioids.[53-55] The
choice of an anaesthetic drug should depend, not
only on its effects on arterial pressure and heart rate,
but also on its peripheral vasodilatory effects and the
ability of the cardiovascular system to counteract
these effects via the baroreflex response. These are
especially important in elderly patients, those with
diabetes-induced neurovegetative dysautonomia
and those receiving drugs that act as antagonists at
the β-adrenoceptor. With regard to such effects,
propofol and thiopental sodium appear to have simi-
lar haemodynamic adverse effects, which differ con-
siderably from those of etomidate and ketamine.
© 2007 Adis Data Information BV. All rights reserved.
705
1.2 Vasodilatation and Baroreflex Response
All anaesthetics, with the exception of etomidate,
induce venous vasodilatation and alter the barore-
flex response.[56,57]
Propofol and thiopental sodium decrease the
slope of the baroreflex;[56,57] with propofol, this ef-
fect depends on the dose and speed of injection,[58]
and the effect is maintained until 1 hour after anaes-
thesia is withdrawn. The effect of these agents is to
reset the y-intercept of the baroreflex slope to the
lowest arterial pressures.[59] The degree of alteration
varies among patients, being sharper in elderly than
younger patients, which explains why there is less
cardiovascular stability following propofol and thio-
pental sodium administration in elderly patients.
Similarly, the pronounced vasodilatation and altered
baroreflex response associated with propofol may
lead to asystole in patients with severe aortic steno-
sis. These effects also explain the poor tolerability of
this drug in hypovolaemic patients.[50,52]
With sevoflurane, the slope of the baroreflex
response is reduced by 50–60% and recovers 120
minutes after hypertension and 60 minutes after
hypotension.[60] These changes, which are observed
during the maintenance of anaesthesia, may be
somehow different to those during induction when
considering the sharp increase in heart rate observed
in some patients.[61] Indeed, previous authors have
observed sympathetic nervous system activation and
a reduction in parasympahetic nervous system activ-
ity.
When the intensity and duration of vasodilatation
and the integrity of the baroreflex are the criteria for
choosing an anaesthetic, especially in elderly or
hypovolaemic patients, induction with 8% sevoflu-
rane might be detrimental. Propofol and thiopental
sodium may be used instead, subject to the dose
being increased in steps to titrate this in accordance
with the cardiovascular effects seen. Propofol must
also be injected slowly.
1.3 Cardiac Output
The maintenance of cardiac output is one of the
main arguments influencing the choice of anaesthet-
ic agent for induction of anaesthesia in patients with
Drugs 2007; 67 (5)
706
cardiac failure or failure of other organs, in which
perfusion pressure and flow maintenance may be
critical to the function of the impaired organ sys-
tems.
Thiopental sodium decreases myocardial con-
tractility dose-dependently in vitro[62] and in
vivo.[63,64] This decrease in myocardial contractility
is greater than that with other anaesthetics.[65] The
thiopental sodium-induced decrease in cardiac out-
put results more from vasodilatation and a decrease
in the baroreflex response than from its direct nega-
tive inotropic effects.[57] This explains why, in cur-
rent clinical practice, some anaesthetists can titrate
thiopental sodium dosages to enable its successful
use for induction of anaethesia in patients with al-
tered cardiovascular status.
Propofol does not exhibit negative inotropic ef-
fects at usual clinical concentrations or dosages[64-67]
in in vitro and in vivo models. In clinical practice,
excessively high concentrations of propofol reduce
cardiac output as a result of sudden and severe
decreases in the precharge and baroreflex slope.
Preoperative haemodynamic status influences
haemodynamic stability after induction of anaesthe-
sia with propofol.[68,69] In patients with cardiac fail-
ure or with coronary artery disease, and in the elder-
ly, titrating the anaesthetic dose using TCI is a
practical means to blunt sudden variations in
precharge and prevent their consequences for myo-
cardial performance and cardiac output.[58]
Despite having negative inotropic effects,
sevoflurane is associated with stable cardiac output
when used at concentrations of up to 2 minimum
alveolar concentrations (MAC), because it main-
tains the postcharge via its vasodilatory effect.[70,71]
On the other hand, halothane, with its greater nega-
tive inotropic effects that are not counterbalanced by
reduced postcharge, may be responsible for cardiac
arrest if too large a dose is administered.[72] The
effects of sevoflurane on diastolic function are con-
troversial and are not criteria in the choice of which
anaesthetic to use for induction, and halothane is no
longer used for induction of anaesthesia in devel-
oped countries.
© 2007 Adis Data Information BV. All rights reserved.
Nathan & Odin
By activating mitochondrial potassium channels,
sevoflurane (as with all the halogenated agents) may
exert a protective effect against myocardial ischae-
mia.[73,74] In in vitro whole heart models, myocardial
contractility is better preserved when sevoflurane is
added to the perfused heart that is to be subjected to
ischaemia.[74,75] In patients with low preoperative
left ventricular ejection fractions, De Hert et al.[76]
observed improved cardiac function and a reduced
need for inotropic agents after coronary surgery
using sevoflurane for induction and maintenance of
anaesthesia compared with using propofol. Similar
results have been seen in other studies, suggesting
that inhalation induction and maintenance of anaes-
thesia with sevoflurane should be favoured for car-
diac surgery over intravenous methods, particularly
in those patients with poor preoperative cardiovas-
cular status.[77-79]
Etomidate is devoid of effects on cardiac output
and myocardial function in patients with and with-
out cardiac disease.[80-82] Despite this apparent lack
of harm, etomidate may alter adrenocortical func-
tion, even after a single dose.[83] Basal cortisol levels
remain unchanged after a single dose of etomidate,
but the cortisol response to adrenocorticotropic hor-
mone is reduced. When there is a relative adrenocor-
tical insufficiency, such as during shock, etomidate
may potentially aggravate this situation. In three
recent studies, a single dose of etomidate used to
allow tracheal intubation proved to be an indepen-
dent risk factor for adrenal insufficiency in an inten-
sive care setting;[84-86] 70% of patients had an altered
response to tetracosactide (tetracosactrin; synac-
then) even as much as 24 hours after etomidate
administration.[85] For clinical purposes, such an ad-
verse effect does not contraindicate the use of etomi-
date in patients with relative adrenocortical insuffi-
ciency, as it has favourable haemodynamic effects,
but one must be cautious and provide supplemental
hydrocortisone to patients as required.
Ketamine has a long history of use because of its
favourable effects on arterial pressure and heart rate
in patients with shock.[87,88] However, this apparent
stability is misleading because the maintenance of
arterial pressure depends on noradrenaline (nore-
Drugs 2007; 67 (5)
Drug Choice for Anaesthesia Induction
pinephrine) release from the sympathetic nerves,
leading to sympathetic stimulation. In patients ex-
periencing prolonged hypovolaemic shock, nora-
drenaline reserves are exhausted and the direct nega-
tive inotropic effect of ketamine may emerge. Simi-
larly, the increase in blood adrenaline (epinephrine)
levels can be harmful in patients with arterial hyper-
tension and coronary disease, as it may lead to
hypertensive crisis and an imbalance between myo-
cardial oxygen consumption and supply.[89-92]
To conclude, etomidate and ketamine might be
favoured for induction of anaesthesia in select cases
(hypovolaemic patients and those in shock), but the
desired effect on the cardiovascular system may be
hampered by adverse effects and the use in combi-
nation with opioids. Despite the usually favourable
effects of ketamine on the cardiovascular system
and its analgesic properties, this agent is no longer
widely used because of its psychological effects
(e.g. nightmares, hallucinations).[93,94] Etomidate
has only weak anaesthetic potency,[95] and anaes-
thetists usually prefer to use a less well tolerated
drug for induction of anaesthesia, and to maintain
cardiovascular equilibrium through cautious use.
The way the drug is administered, rather than the
choice of a specific drug, is the main factor in
maintaining haemodynamic stability and obtaining
deep anaesthesia during induction. The ease with
which the latter can be modulated by varying the
dose and the speed of injection with TCI systems is a
major factor when choosing an anaesthetic drug.
2. Equipment and Anaesthetic
Technique as a Factor in Drug Choice
The choice of agent for induction of anaesthesia
made by some anaesthetists is guided by the availa-
bility of TCI systems. A priori, all anaesthetics may
be administered as a TCI using software only availa-
ble for research purposes (e.g. Stanpump®,
Rugloop©)1. However, in everyday clinical prac-
tice, only propofol, remifentanil and sufentanil can
be administered by TCI using commercial software
connected to specific pumps. There are several argu-
1 The use of trade names is for product identification purposes only and does not imply endorsement.
© 2007 Adis Data Information BV. All rights reserved.
707
ments for TCI use during the induction of anaesthe-
sia. The ease with which anaesthesia is induced and
maintained with the same agent, particularly when
the airway is unavailable (e.g. for ear, nose and
throat [ENT] endoscopy), is frequently men-
tioned.[96] The ease with which the depth of anaes-
thesia can be precisely determined and adjusted, and
the ability to reduce the interindividual variability of
the hypnotic effect are other advantages of TCI
anaesthesia.[97,98]
Several studies suggest a better haemodynamic
tolerability of TCI propofol compared with manual
adjustments of the propofol dosage,[96,99] but this has
some exceptions. TCI does not improve cardiovas-
cular stability during anaesthesia with propofol if
the user targets an a priori fixed concentration.
When the target concentration is fixed at a predeter-
mined level, delivered as a bolus or delivered to
elderly patients and those with cardiovascular dis-
eases, the cardiovascular equilibrium is not better
maintained with TCI than after administration of a
bolus dose calculated on the basis of weight. When
TCI is used in such a setting, it is associated with
worse cardiovascular stability than a continuous in-
fusion with gradual increases of blood concentra-
tions of the drug.[100-102] In other studies, manually
adjusted doses and TCI propofol similarly altered
arterial pressure and heart rate.[103,104] These appar-
ent discrepancies are easy to understand: after a
manually administered or TCI bolus, the cardiovas-
cular system is unable to adapt itself to the sudden
variations in precharge because of propofol-induced
alteration in the baroreflex. Ideally, an opioid must
also be administered by TCI unless instability in
arterial pressure is observed.
In patients scheduled for carotid surgery, TCI
propofol and remifentanil reduced the incidence of
hypotension by half compared with TCI propofol
and weight-adjusted boluses of remifentanil.[105] To
avoid hypotension, the balance between propofol
and opioid target concentrations must favour a
higher concentration of propofol and a lower con-
centration of opioids. During carotid surgery, when
the remifentanil target concentration is adjusted to
Drugs 2007; 67 (5)
708
haemodynamic variations and bispectral index val-
ues, the fall in arterial pressure is not greater with a
propofol target concentration of 2.4 mg/L than with
a target concentration of 1.2 mg/L.[106] However,
under these circumstances, tachycardia is more fre-
quent. Similarly, the decrease in heart rate at loss of
consciousness is greater when propofol at a low
concentration is combined with alfentanil at a high
concentration than when propofol at a high concen-
tration is coadministered with alfentanil at a low
concentration.[107] Targeting the effect-site concen-
tration instead of the plasma concentration hastens
the speed of induction without altering haemody-
namics in otherwise healthy patients.[108,109] Com-
pared with manual adjustments, the depth of anaes-
thesia with propofol can be more easily and precise-
ly adjusted using TCI. This can limit haemodynamic
variations during cardiac surgery in patients with
good left ventricular systolic function.[110] This ease
of practice is also observed during ENT endoscopic
procedures, where arterial pressure variations can be
reduced from 20% to 10% by titrating propofol to
target concentrations.[96]
In elderly patients undergoing hip fracture sur-
gery who were anaesthetised using propofol TCI
titration, arterial pressure remained within 15% of
preanaesthetic values for 60% of the time, but only
remained within such a range for 30% of the time
when with propofol concentrations were adjusted
manually.[99]
In brief, most of the cardiovascular adverse ef-
fects associated with induction of anaesthesia result
from the combination of anaesthetics with opioids
and the doses of the latter.
There is neither a miraculous drug nor a better
technique that must be favoured to improve
haemodynamic stability during induction of anaes-
thesia. For this reason, if sevoflurane inhalation is
chosen as the means of inducing anaesthesia, the
anaesthetist should favour low opioid doses and will
have to be prepared to rapidly reduce the vapouriser
settings. If intravenous propofol is chosen, its dose
and speed of infusion may need to be reduced,
preferably by titration against the cardiovascular
effects. TCI may thus be used because it reduces
© 2007 Adis Data Information BV. All rights reserved.
Nathan & Odin
interindividual variability and adjusts circulating
blood concentrations more precisely and rapidly
than manual adjustments.[97,98] Etomidate is the drug
of choice in patients with impaired cardiovascular
function and those who are in hypovolaemic shock.
However, cortisol synthesis will be altered for the 24
hours immediately following a single etomidate
dose. Ketamine may be used for the same purpose,
but is associated with adverse psychological effects
that preclude its current clinical use.
3. Choice of an Induction Agent for
Upper Airway Control
The choice of a drug for induction of anaesthesia
depends on the technique planned for control of the
airway. Other factors, such as the neuromuscular
blocking agents (NMBs) required for surgery and
the speed of onset needed for securing the airway,
also influence the choice of agent.
3.1 Intubation Using Neuromuscular Blocking
Agents (NMBs)
When an NMB is required for surgery, the
clinical outcomes sought are to achieve good intuba-
tion conditions, avoid awareness during induction,
and minimise cardiovascular responses to intuba-
tion. Even if a myorelaxant is used, conditions for
intubation depend on the depth of anaesthesia.[111]
An adequate depth of anaesthesia without awareness
can be obtained for 5 minutes in 50% of the patients
receiving thiopental sodium for induction of anaes-
thesia. This time without awareness is increased to 9
minutes if patients receive propofol.[37] This sug-
gests that awareness may occur more often in pa-
tients receiving a thiopental sodium-NMB combina-
tion than in those receiving an propofol-NMB com-
bination, even if the time elapsed between induction
and intubation is short.[112] This time difference thus
favours the use of propofol to avoid awareness. The
short duration of thiopental sodium limits its adverse
cardiovascular effects. Indeed, with its short dura-
tion of action, the thiopental sodium-induced de-
crease in arterial pressure will be of similar duration
and/or lesser magnitude than that associated with
propofol.[36] However, all these differences between
Drugs 2007; 67 (5)
Drug Choice for Anaesthesia Induction
propofol and thiopental sodium are decreased by the
combination of these agents with moderate doses of
opioids.[25,113]
3.2 Intubation Without NMBs
NMBs are the primary cause of anaesthesia-asso-
ciated anaphylaxis. This is why most anaesthetists
avoid using them to facilitate intubation when they
are not required for surgery. This may occur in as
many as 68% of cases.[114] To enable intubation
without NMBs, only anaesthetics that can relax the
masseter muscle and vocal cords, such as propofol,
should be used for induction of anaesthesia.[115,116]
The conditions for intubation will still depend on the
depth of anaesthesia, but the bispectral index value
is not able to predict intubation-triggered
cough.[46,117,118]
With thiopental sodium 5 mg/kg, only poor con-
ditions for intubation are obtained, resulting in a
successful intubation rate of only 66%. This rate
falls to 33% with thiopental sodium 4 mg/kg.[119] In
a study of thiopental sodium 6 mg/kg and etomidate
0.3 mg/kg, intubation was not possible in 3/15 and 5/
15 patients, respectively, even when these drugs
were used in combination with remifentanil 3 μg/
kg.[116] Excellent or good conditions for intubation
were observed in only two-thirds of patients who
received thiopental sodium and one-third of the pa-
tients who received etomidate, but occurred in 93%
of patients who received propofol.[116]
For tracheal intubation, a propofol-opioid combi-
nation or sevoflurane with or without coadministra-
tion of an opioid, can be used with high rates of
success and low incidences of respiratory adverse
events.[120-123] However, with these two techniques
the rates of success do not reach 100% and the time
to achieve good conditions of intubation exceeds
that obtained with a anaesthetic-suxamethonium
chloride (succinylcholine chloride) combination,
thus contraindicating these techniques for rapid se-
quence induction.[46,113] The wider vocal cord open-
ing achieved with propofol compared with thiopen-
tal sodium or etomidate confirms the better condi-
tions for intubation obtained with this drug and
favours its use.[115,116] However, even with propofol,
© 2007 Adis Data Information BV. All rights reserved.
709
high opioid doses are required to avoid gagging and
coughing upon intubation. Alfentanil 40 μg/kg or
remifentanil 4 μg/kg must be combined with pro-
pofol in order to obtain conditions for intubation
similar to those achieved with an anaesthetic-sux-
amethonium chloride combination.[124,125] However,
this will be at the price of severe bradycardia, hypo-
tension and a prolonged duration of ap-
noea.[116,124-127] The similar times to cerebral peak
concentrations for propofol and alfentanil (90 and
120 seconds, respectively) favour the use of this
combination in clinical practice.[128,129]
Remifentanil, with the same time to peak effects
at 1 and 4 μg/kg dosages, is also the drug of choice
when induction and intubation without NMB is
planned. Lower remifentanil doses (1 μg/kg) may be
used, and achieve an acceptable success rate.[25] For
other opioids, the required doses are similar to those
used with alfentanil, but must be injected earlier to
account for the 5- to 6-minute times to cerebral peak
concentrations.[130]
Conditions for intubation judged as good or ex-
cellent are obtained in 93% of patients treated with
sevoflurane alone and 95% of patients who receive
the combination of thiopental sodium and sux-
amethonium chloride.[131] However, although induc-
tion of anaesthesia lasted three times as long with
sevoflurane than thiopental sodium-suxamethonium
chloride, and vocal cord opening was worse, pa-
tients better maintained spontaneous ventilation.[121]
These results have led clinicians to use sevoflurane
for induction of anaesthesia in cases where tracheal
intubation is difficult, with similar success rates to
those achieved with propofol alone.[132,133] By ad-
ding small doses of opioids to sevoflurane (al-
fentanil 10 μg/kg or an equivalent dose of another
opioid), the time to intubation can be reduced from
5–6 minutes to 3 minutes, the conditions for intuba-
tion are improved and the cardiovascular conse-
quences of intubation and induction of anaesthesia
are minor.[46,122] Only high doses of opioids are able
to completely prevent coughing upon intubation, but
this is achieved at the cost of haemodynamic stabili-
ty.[45,134] In combination with 8% sevoflurane,
remifentanil 2 μg/kg achieved better conditions for
Drugs 2007; 67 (5)
710
tracheal intubation than using remifentanil 1 μg/kg,
but a fall in arterial pressure of greater than 30% was
observed.[121] Following induction of anaesthesia us-
ing 8% sevoflurane and remifentanil 1 μg/kg, 4% of
the patients coughed severely, bit the tube or exhib-
ited mandibular rigidity after tracheal intubation.
Sivalingam et al.[135] combined alfentanil 10, 20, 25
or 30 μg/kg with 8% sevoflurane in 60% nitrous
oxide for intubation after loss of eyelash reflex. The
conditions for intubation 90 seconds later were simi-
lar between alfentanil dosages, but the decrease in
mean arterial pressure was lowest in the alfentanil
10 μg/kg group. As mentioned above, the lowest
dosages of opioids can greatly reduce the time to
intubation; however, NMBs may be still required
because coughing may occur in up to 70% of pa-
tients receiving the lowest opioid dose, whereas
vocal cord closure occurs after administration of
higher opioid doses.[40] Fentanyl 1 μg/kg and al-
fentanil 10 μg/kg are optimal doses because they are
the best compromise between haemodynamic stabil-
ity and ideal conditions for intubation; however,
NMBs may still be required with such doses.
When intubation without an NMB is planned, a
propofol-opioid combination clearly gives the better
clinical conditions. However, this is at the price of a
greater risk of adverse cardiovascular effects.
Sevoflurane alone may be an alternative, but results
in a longer duration of induction.
3.3 Crash Induction
For crash induction, the choice of agent is usually
based on the pharmacokinetic properties of the an-
aesthetic. Thus, the peak cerebral concentrations of
the anaesthetic and suxamethonium chloride –
which provides, in 60 seconds, the best conditions
for glottis exposure – must be superimposed to
avoid either an excessive depth of anaesthesia or
awareness.[136] For a rapid induction-intubation se-
quence, only thiopental sodium and etomidate fit
this criterion. Time to propofol cerebral peak effect
occurs slightly later, after 2–3 minutes, whatever the
rate of propofol injection (within clinically appro-
priate limits).[137] The blood-brain equilibration half-
lives of thiopental sodium and propofol are 1.22 and
© 2007 Adis Data Information BV. All rights reserved.
Nathan & Odin
4.32 minutes, respectively.[138] The times to thiopen-
tal sodium cerebral peak effect were 1.5 and 2.75
minutes when injected over 10 seconds and 2 min-
utes (an inappropriately long duration of injection),
respectively, whereas the times to cerebral peak
effect for propofol were 2.75 and 4 minutes after this
drug was injected over the same intervals.[138] Thus,
with propofol, anaesthetists must increase the dose
and the speed of injection to reach a cerebral con-
centration and depth of anaesthesia that are adequate
for suppression of the intense stimulus of tracheal
intubation. The price to pay is large haemodynamic
variations, particularly in elderly patients or those
with particular cardiovascular risk factors.[113]
The choice of an anaesthetic for crash induction
may, contrary to the pharmacokinetic argument
presented above, favour propofol instead of thiopen-
tal sodium owing to their different pharmacodynam-
ic properties. Some anaesthetists may prefer pro-
pofol instead of thiopental sodium to avoid an ex-
cessive increase in intraocular pressure before open-
eye surgery. Indeed, after administration of a thio-
pental sodium-suxamethonium chloride combina-
tion, intraocular pressure is transiently increased,
whereas it is maintained or decreased following the
propofol-suxamethonium chloride combination.[139]
In clinical practice, the choice of an anaesthetic
drug to use in combination with suxamethonium
chloride for crash induction has little influence on
the quality of intubation conditions if the NMB
doses are higher than 2DA95 (i.e. greater than two
times the dose of NMB required to decrease the
force of contraction of the adductor pollicis muscle
following ulnar nerve stimulation by 95%). During a
rapid induction-intubation sequence, the aim of the
anaesthetic is to avoid awareness and to limit the
hypertensive response to intubation. Time to a bis-
pectral index value <60 is shorter with thiopental
sodium, but so is the duration of deep anaesthe-
sia,[37] thus exposing the patient to the risk of aware-
ness and memories of surgery. A bispectral index
value >60 is more often observed with thiopental
sodium than propofol during crash induction.[112]
With a propofol-opioid combination, the arterial
pressure increase following intubation is lower than
Drugs 2007; 67 (5)
Drug Choice for Anaesthesia Induction
that after a thiopental sodium-suxamethonium chlo-
ride sequence. However, by adding an opioid to
treatment, the differences between the two drug
combinations are decreased.[25]
For reduction of the hypertensive peak induced
by intubation, the choice of opioid and its dose are
probably more important factors to take into account
than the type of anaesthetic. For this purpose, a fast-
acting opioid such as alfentanil or remifentanil,
where the times to peak cerebral effects are between
1 and 1.5 minutes after administration, might be
preferred to limit the rise in the arterial and intraocu-
lar pressures.[25,140] Remifentanil, with its short dura-
tion of action in adults and children, has also been
used in the performance of caesarean sections
(mainly in women who are pre-eclamptic) to avoid
the deleterious effect of hypertension before intuba-
tion and skin incision.[141-143] However, the addition
of remifentanil to a thiopental sodium-suxamethoni-
um combination is associated with greater respirato-
ry depression in the newborn compared with when
remifentanil is not used.[144] When propofol is used
for induction of anaesthesia before caesarean sec-
tion, the Apgar scores of the newborn at birth are
lower than those observed after thiopental sodi-
um.[145,146] The thiopental sodium-suxamethonium
chloride combination thus remains the recommend-
ed partnership for induction of anaesthesia in caesa-
rean section, instead of propofol-suxamethonium
chloride.
3.4 Laryngeal Mask Insertion
The ideal anaesthetic drug for laryngeal mask
insertion should have pharyngo-laryngeal relaxant
effects and avoid glottis closure. For this indication,
propofol in combination with an opioid and
sevoflurane alone or combined with small doses of
opioids are currently chosen by anaesthetists.[147,148]
Thiopental sodium alone does not allow for easy
laryngeal mask insertion;[149,150] conditions for in-
sertion may be improved by adding small doses of
NMB.[151] However, adverse effects have been ob-
served in 76% of patients who have received thio-
pental sodium and 24–36% of patients who received
propofol administered alone.[47,150] By adding an
© 2007 Adis Data Information BV. All rights reserved.
711
opioid, propofol anaesthesia becomes adequate to
allow correct insertion of a laryngeal mask in most
cases.[152,153] Ideally, the maximal peak effects of the
anaesthetic and the opioid should coincide to op-
timise the effects of the combination.[154] Small
opioid doses may induce excellent conditions for
insertion; administration of alfentanil 5 μg/kg pro-
vided excellent conditions for laryngeal mask inser-
tion in 90% of treated patients.[155] The 1–2 minutes
of waiting time before the desired effect is short, and
corresponds to the maximum times to peak effect of
propofol and alfentanil.
However, with sevoflurane, adding an opioid is
not required to obtain good conditions for laryngeal
mask insertion in almost 100% of patients. When
mandibular relaxation is achieved and patients can
tolerate three manual insufflations of the trachea,
then the success rate for laryngeal mask insertion
with sevoflurane reaches 100%.[156] In 95% of pa-
tients who have received sevoflurane for induction
of anaesthesia, laryngeal masks may be inserted
after a mean time of 2.4–2.7 minutes and a maxi-
mum 4.4-minute delay.[157-159] Adding an opioid to
anaesthesia with sevoflurane at the time of loss of
eyelash reflex does not reduce the time to insertion
of the laryngeal mask.[47] The incidences of cough-
ing and laryngospasm tend to be reduced by adding
fentanyl.[159] The ease of laryngeal mask insertion
following induction of anaesthesia with sevoflurane
is also improved with alfentanil 5 μg/kg.[47] Adding
nitrous oxide to anaesthesia with sevoflurane does
not improve conditions for laryngeal mask inser-
tion.[160]
A recent meta-analysis comparing propofol and
sevoflurane for induction of anaesthesia with laryn-
geal mask insertion supported the superiority of
sevoflurane.[161] The rate of success at first attempt
was higher with sevoflurane than propofol (odds
ratio 2.37; 95% CI 0.52, 10.88). Adverse respiratory
effects were similarly reduced when using
sevoflurane instead of propofol. However, transient
jaw tightness associated with sevoflurane may delay
the insertion of the laryngeal mask.[162]
Maintenance of spontaneous ventilation occurs
more often in patients receiving sevoflurane than
Drugs 2007; 67 (5)
712
those receiving propofol.[121,163] This avoids the use
of controlled positive pressure ventilation after la-
ryngeal mask insertion and reduces the incidence
and severity of leaks through the laryngeal mask.
However, not all authors observe this superiority
with sevoflurane, probably because the success of
the inhalation technique relies on training and expe-
rience.[162,163] Clearly, for induction of anaesthesia
and laryngeal mask insertion, sevoflurane is the
drug of choice.
4. Patients with Increased
Intracranial Pressure
Propofol, etomidate and thiopental sodium all
decrease cerebral metabolism, oxygen consumption,
middle cerebral artery velocity or flow and in-
tracranial pressure (ICP).[164-166] The decrease in ICP
results from increased vascular cerebral resistance
and decreased intracranial blood volume. All three
drugs preserve reactivity of the cerebral perfusion
rate in response to arterial carbon dioxide
levels.[164-166] However, this apparent beneficial ef-
fect is limited by the effects of opioids on mean
arterial pressure and cerebral perfusion pressure
(CPP), which are important prognostic factors for
impaired outcomes.[167] An excessive decrease in
CPP may trigger cerebral vasodilatation and in-
crease ICP, limiting the effect of the drug on
ICP.[168] The suitability of these drugs in a
neurosurgical setting thus depends on the way in
which they are administered. Continuous infusion of
propofol is favoured over bolus dose injection.[169]
Slight differences exist between the abilities of these
three drugs to decrease ICP. Thiopental sodium has
a dose-dependent effect culminating in a 50% de-
crease in ICP, with tolerability increased by pro-
longed perfusion. Cerebral vasoconstriction induced
by propofol similarly reduces ICP, and a limited
additional benefit is possible when this drug is used
in combination with hyperventilation, as long as
hyperventilation is started before propofol infu-
sion.[170,171] Etomidate, when titrated to obtain sup-
pression of EEG bursts, similarly lowers ICP by
© 2007 Adis Data Information BV. All rights reserved.
Nathan & Odin
50% while preserving CPP.[172] However, in a study
by Modica and Tempelhoff,[172] high doses of etomi-
date (mean 1.28 mg/kg dose over 4 minutes), with
their potentially deleterious effects on cortisol syn-
thesis, were necessary to obtain this decrease.
On the other hand, ketamine is known to increase
middle cerebral artery velocity/flow and ICP, sug-
gesting that this drug should not be used for induc-
tion of anaesthesia.[173-175] This adverse effect occurs
due to respiratory depression in the presence of
intracranial hypertension,[173] and is not observed
when GABA agonists are coadministered.[176-178] In
patients sedated with propofol for whom carbon
dioxide partial pressure was controlled, ketamine 3
and 5 mg/kg decreased cerebral metabolism, oxygen
consumption and ICP by approximately 30%, while
maintaining CPP.[177] The beneficial effect of
ketamine on haemodynamics and its neuroprotec-
tive action suggest that it can be used in patients
with brain insult as long as moderate hypocapnia is
maintained. However, these studies were performed
in an intensive care setting, and their results cannot
be transposed to the induction of anaesthesia.
The dose-related cerebral vasodilatation induced
by high concentrations of sevoflurane contraindi-
cates this anaesthetic for induction of anaesthesia in
patients with increased ICP.[179]
To summarise, propofol and thiopental sodium
are suitable for induction of anaesthesia in neurosur-
gery. However, the ability of these drugs to lower
ICP while maintaining CPP depends on stable
haemodynamics. The choice of thiopental sodium
for induction may be favoured if halogenated agents
can be used to maintain anaesthesia, otherwise pro-
pofol should be used. When ICP is increased, infu-
sion instead of bolus injection of propofol is the best
choice to induce and maintain anaesthesia without
altering times to awakening and the results of neuro-
logical evaluations. In already haemodynamically
unstable patients, etomidate can be used to optimise
ICP and CPP, but this requires the use of high doses,
which are associated with a considerable risk of
depression of cortisol synthesis.
Drugs 2007; 67 (5)
Drug Choice for Anaesthesia Induction
5. Patient Satisfaction and Quality
of Awakening
The agent used for induction of anaesthesia, on
its own, has been found to have little influence on
levels of patient satisfaction, which may be equally
high regardless of the drug or the technique used for
induction: 95–100% of the patients would accept the
same method of induction for future anaesthesia in
most studies.[5,38,180-182] However, others do not find
such a high level of satisfaction: 22% of patients
receiving sevoflurane induction expressed a prefer-
ence for another type of anaesthesia, compared with
only 3% of those receiving propofol. One must be
aware that, in this study,[183] only 71% of patients
were satisfied with propofol induction of anaesthe-
sia and the incidence of postoperative nausea and
vomiting (PONV) was high in patients receiving
sevoflurane. A trend towards lower indices of satis-
faction is observed in some population subgroups,
such as the elderly and patients with a high risk of
PONV.[183,184] Such differential satisfaction between
patient groups was found in the meta-analysis by
Joo et al.[161] In some patients with claustrophobia,
an intravenous technique should be favoured,
whereas in patients who fear needles, an inhalation
technique may be proposed. Patient satisfaction also
results from the quality of explanations given before
surgery or anaesthesia and the ability of anaes-
thetists to respect patient choices and expectations.
When 240 patients were asked what they would
prefer for their anaesthesia, 50% chose an inhalation
technique, 33% an intravenous technique, and 17%
were undecided.[185]
Many studies dealing with patient satisfaction
with anaesthesia are carried out in the context of
strict protocols and in highly selected patients who
are rigorously observed. This can affect their level
of satisfaction, which may be higher than in current
clinical practice. Currently, no studies have been
published that have compared patient satisfaction
with induction of anaesthesia via inhalation of
sevoflurane with that associated with intravenous
induction in clinical care. To answer this question in
current clinical practice, one must know which ad-
verse effects the patients fear the most; awakening
© 2007 Adis Data Information BV. All rights reserved.
713
during surgery, PONV, postoperative pain and
drowsiness are the four items that are the most often
pointed out by patients, whatever their experiences
of anaesthesia.[186,187]
The risk of awareness is theoretically higher with
thiopental sodium, but despite shorter recovery
times, no differences in peroperative memories have
been observed.[37] However, continuous infusion or
TCI propofol and sevoflurane inhalation induction
should be favoured if a risk of awareness is antici-
pated, such as in highly anxious patients with high
cardiac output or in cases of anticipated prolonged
intubation. Indeed, with halogenated agents, aware-
ness is suppressed from a dose corresponding to
0.45 MAC.[188] Thus, perioperative memories are
highly improbable with induction of anaesthesia
using sevoflurane, especially since sevoflurane con-
centrations are maintained by continuous inhalation
and end-tidal expired sevoflurane concentrations are
monitored. When agents for induction of anaesthe-
sia are administered by the intravenous route, drug
concentrations may diminish rapidly following in-
jection of bolus doses, or the TCI device may break
down. Continuous analysis of expired sevoflurane
allows the delivery of anaesthetic by the vapouriser
to be checked, thus avoiding overdosage or un-
derdosage. The breakdown of intravenous infusion
devices may remain undiagnosed, leading to patient
awakening.[189] The highest risk of awareness is
associated with use of etomidate. Indeed, as many as
65% of cases of awareness in patients may be ob-
served during intubation following a clinical dose of
etomidate.[95]
Propofol, with its antiemetic properties, is
thought to be a better choice for induction of ambu-
latory anaesthesia. However, the protective effect of
propofol against PONV is only observed during the
first 6 postoperative hours when propofol is used as
the sole anaesthetic for both induction and mainte-
nance.[190] Indeed, the antiemetic properties of pro-
pofol depend on the persistence of low blood pro-
pofol concentrations. The incidences of PONV are
similar after induction of anaesthesia with propofol,
thiopental sodium and etomidate, if anaesthesia is
maintained with a halogenated agent.[191] Thiopental
Drugs 2007; 67 (5)
714
sodium has no effect on emesis. Etomidate increases
the risk of postoperative emesis, as does sevoflurane
inhalation induction.[161] The incidence of PONV
after an inhalation induction ranges from 11% to
50%.[181,183,192] However, this has no consequence
on the time to discharge from following ambulatory
anaesthesia.[5,181] Some anaesthetists use specific
prophylaxis against PONV to enable the use of less
expensive drugs for the induction of anaesthesia.
Indeed, propofol TIVA, which is the optimal
method for preventing PONV, is two to three times
more expensive than inhalation anaesthesia when
each of these are used for both induction and mainte-
nance of anaesthesia.[38,193]
Severe pain associated with propofol injection
also causes high levels of patient dissatisfaction,
which may lead patients to ask for a change of
anaesthesia for future surgeries.[181,194,195] Such pain
is also associated with injection of etomidate; it has
been observed in 11–69% of patients receiving
etomidate, and was remembered by 50% of pa-
tients.[163,181,194,195] A new propofol formulation has
been developed to reduce the risk of injection pain,
although this can already be partly controlled by
mixing lidocaine with propofol.[195] The formulation
of etomidate has been changed for the same purpose.
The only risk for dissatisfaction during inhalation
induction results from the smell of sevoflurane,
which is judged to be unpleasant by <20% of pa-
tients.[181,196]
A quality of awakening that allows patients to
undertake their everyday activities or complex ac-
tions, and a short time to awakening are two impor-
tant criteria for methods and drugs used for induc-
tion in ambulatory anaesthesia. Compared with pro-
pofol, thiopental sodium used for short-duration
ambulatory anaesthesia increases the length of stay
in the recovery room and decreases scores on mental
status tests during recovery, leading to a delay in
discharge from hospital.[197,198] For anaesthesia of
longer duration, mental status test results during
intermediate and late recovery are similar following
induction of anaesthesia with thiopental sodium and
propofol, and the time to discharge home is similar
regardless of which drug was used for induction of
© 2007 Adis Data Information BV. All rights reserved.
Nathan & Odin
anaesthesia.[199] However, for the past 15 years pro-
pofol has been considered the ideal choice for ambu-
latory anaesthesia. Sevoflurane inhalation induction
may change this practice because its pharmacokinet-
ic properties allow rapid recovery after its use.
Sevoflurane is eliminated by the respiratory route
and does not require metabolism to for rapid elimi-
nation.[200] Bailey[201] thus observed sevoflurane
context-sensitive half-lives that were independent of
the duration of surgery and far lower than those for
intravenous anaesthetics. As a result, the recovery
after sevoflurane induction and maintenance is
sometimes of better quality and faster, with less
interindividual variability in these parameters, than
after induction of anaesthesia with pro-
pofol.[38,184,197,202-205]
To conclude, sevoflurane induction is better than
a propofol bolus dose for avoiding the risk of awak-
ening. However, with its shorter duration of induc-
tion and its effects on PONV, propofol is usually
preferred by anaesthetists. Sevoflurane and propofol
appear equivalent for obtaining a good quality of
recovery.
6. Cost of Anaesthesia as a Criterion for
Drug Choice
The use of the older anaesthetics, thiopental sodi-
um and fentanyl, is clearly associated with lower
acquisition costs for anaesthesia compared with
newer drugs such as propofol, sevoflurane,
remifentanil and sufentanil). Several studies have
shown that induction and maintenance of anaesthe-
sia with sevoflurane is less expensive than with
propofol, but this is only true if fresh gas flows
(FGF) are strictly controlled during induc-
tion.[38,181,182,193,203-205] Most of these studies do not
differentiate the cost of induction and the cost of
maintenance, mainly because they used closed cir-
cuit delivery from the start of anaesthesia and did
not quantify the cost of wasted drugs, such as pro-
pofol, at the end of induction nor did they quantify
the cost of single-use equipment. The costs of anaes-
thetic drug waste account for 18–40% of total intra-
operative costs.[206,207] Costs for anaesthetic drug
Drugs 2007; 67 (5)
Drug Choice for Anaesthesia Induction
wastage and disposable equipment are highest with
propofol and lowest with sevoflurane.[193]
The cost of anaesthesia cannot be transposed
from one institution and/or one country to another,
because of the differing costs of drugs and other
medical resource use. Also the introduction of ge-
neric drugs is responsible for a dramatic fall in the
cost of propofol, the current most commonly used
comparator.
Because of the different prices of sevoflurane all
around the world, it is better to compare the quantity
of liquid sevoflurane used for induction. In theory,
this amount (in mL) can be calculated by multiply-
ing the sevoflurane concentration delivered by the
vapouriser by the FGF (in mL) and the time elapsed
in minutes, and dividing by 183 (the number corre-
sponding to the amount of vapour [in mL] produced
by 1mL of liquid sevoflurane). Employing this
formula for a typical induction of 5 minutes dura-
tion, with a 4 L/min FGF and using 8% sevoflurane,
yields consumption of 8.7mL of liquid
sevoflurane.[208] This calculation does not take into
account the gas for circuit preparation, leaks or FGF
variations that are associated with a real induction.
In clinical practice, the consumption of
sevoflurane depends mainly on the FGF and the use
of other drugs that reduce the duration of induc-
tion.[193,197] Smith et al.[193] measured consumption
of 8.52 ± 0.44mL of sevoflurane when using a 6 L/
min FGF, while Fleishmann et al.[197] observed con-
sumption of 7.2mL of sevoflurane using a vital
capacity technique and a 8 L/min FGF. The latter
technique, with the addition of a reservoir bag, re-
duced the amount of sevoflurane spent to 3.2mL. In
these two studies, fentanyl 1 μg/kg was used and a
laryngeal mask was inserted.
By avoiding circuit priming with sevoflurane,
drug consumption may be reduced from 8mL to
4.4mL, without consequences for the time to obtain
adequate anaesthesia.[196] For tracheal intubation,
which takes longer, sevoflurane consumption
should be higher; consumption of 12mL of
sevoflurane has been measured during cases of stan-
dard or difficult tracheal intubation.[133,182] Reduc-
tion of the FGF and closure of the vapouriser when
© 2007 Adis Data Information BV. All rights reserved.
715
manipulating the airway allows cost containment.
With the introduction of a new anaesthesia machine
(Zeus®, Drager Inc.), halogenated agents may be
administered to achieve an expired end-tidal con-
centration target. The software calculates the FGF
and the anaesthetic dose to be injected into the
circuit in order to achieve the desired end-tidal con-
centration. This frees the user from operating the
FGF and vapouriser setting controls. With this tech-
nique, however, gas and sevoflurane consumption
for induction of anaesthesia are similar or higher
than those used with a standard circle system, in
which the consumption of gas and anaesthetic
vapours are increased in response to measurements
of their inspired and expired concentrations.[209]
The use of the circle system, allows the practice
of ‘overcasting’, as described by Hendrickx et
al.[210,211] This consists of reducing the FGF to val-
ues close to those needed for patient consumption
(approximately 200–500 mL/min oxygen) after in-
duction and turning off the vapouriser. With this
technique, anaesthesia may be maintained for 20
minutes after induction without turning the
vapouriser on again.
The direct costs of drugs and single-use equip-
ment represent only 9% and 16% of the total cost of
anaesthesia, respectively, whereas the costs of
wages and salaries are more than 61–80%, depend-
ing on social policies.[212] Only 3% of the costs of
anaesthesia can be modulated by a cost-containment
policy.[213] A reduced duration of induction may
indirectly affect staffing costs. Whereas the number
of nurses cannot be reduced in most cases, their
productivity can be improved. Reducing the time
taken for induction of anaesthesia only has cost
consequences for short-duration anaesthesia where
the number of procedures performed daily may be
increased.[214] For example, reducing the duration of
induction by 2 minutes (which is the difference in
duration between intravenous and inhalation induc-
tion) in a 15-minute anaesthesia allows the treatment
of one more case every 2 hours. This favours the use
of propofol instead of sevoflurane for short-duration
procedures. Similarly, a reduction in the time to
awakening cannot be translated to a reduction of
Drugs 2007; 67 (5)
716
recovery room costs. Reduction in recovery costs
depends on the estimated recovery time and the
ability for a patient to bypass the recovery room stay
if there is no legal requirement for it. Compared with
intravenous induction of anaesthesia, inhalation in-
duction and maintenance might increase the turno-
ver of patients in the recovery room and, in theory,
reduce the number of staff needed. However, a stay
in the recovery room is not only necessary for awak-
ening but also to treat any adverse effects of surgery
and anaesthesia, such as pain and PONV. The
choice of drug used for induction of anaesthesia
influences the time to awakening only for short-
duration procedures (those lasting less than 20–30
minutes). For longer-lasting surgery, the choice of
drug for has no effect.[214] For short durations of
anaesthesia, when the duration of stay in the recov-
ery room is 15 minutes, reducing the time to awak-
ening by 2 minutes, allows one more patient to
receive care in the recovery room every 2 hours.
For a longer recovery room stay of 1–2 hours, a
10-minute reduction in the duration of stay should
only increase the turnover of patients by one every
6–12 hours. The reduction in the duration of stay
would have to be at least 30 minutes to allow the
care of one more patient every hour or to plan staff
reduction in recovery rooms dealing with eight or
more patients every hour.
The willingness-to-pay for avoidance of adverse
events, such as PONV, exceeds the extra cost of
newer agents, such as propofol. Patients might agree
to pay $US34 (2003 values) to avoid awareness.[215]
However, this willingness-to-pay for changes in
quality of life shows large variations between pa-
tients and cultures,[216] which precludes the world-
wide validity of cost-benefit or cost-effectiveness
studies. This willingness-to-pay also differs accord-
ing to who is paying the bill. For example, patients
would agree to pay $US43 instead of $US34 to
prevent a very rare event, such as awareness, if they
were reimbursed by the insurance company.[217] In
another recent study, patients were willing to pay
only $US17 for a drug that prevented PONV after
surgery.[218] However, in that study there was a large
variability in results, with willingness-to-pay rang-
© 2007 Adis Data Information BV. All rights reserved.
Nathan & Odin
ing from $US7 to $US69 according to psychological
factors and the patient’s history of PONV. The mean
willingness-to-pay of $US17 seen in this study was
far less than the $US50 and $US100 reported by
Orkin[219] and Macario et al.,[220] respectively. In-
comes may affect the willingness-to-pay to prevent
PONV, as does the way the question is asked, how it
is emphasised, and the severity and duration of this
adverse effect.[187] The incidence of PONV may also
affect the cost-effectiveness ratio when comparing
induction and maintenance of anaesthesia with pro-
pofol alone, sevoflurane alone, propofol and
sevoflurane, or propofol and isoflurane.[221]
To summarise, the cost of drugs for the induction
of anaesthesia must be considered negligible com-
pared with the other costs of anaesthesia. When
using sevoflurane for induction, the price of anaes-
thesia is far lower than that with propofol, but only if
severe containment of FGF is undertaken.
7. Conclusion
Despite numerous arguments to rationalise the
choice of a drug for induction of anaesthesia, most
of the time the use of a specific drug is guided by the
habits of anaesthetists. However, the way they ad-
minister the drug will change according to the pa-
tient’s status. If the practitioner aims at cardiovascu-
lar stability, a progressive and titrated dose of both
an opioid and an anaesthetic will be the best way to
achieve this goal, rather than the use of a specific
drug. For ambulatory anaesthesia, propofol or
sevoflurane will allow a rapid discharge from hospi-
tal. In patients with a high risk of PONV, propofol
will be a better choice than sevoflurane, but only for
short-duration anaesthesia. For laryngeal mask in-
sertion, sevoflurane seems to be a better choice than
a propofol-opioid combination. When performing
tracheal intubation without a NMB, a propofol-
opioid association is often preferred to sevoflurane
because of the increased duration of induction and
despite similar conditions of intubation. The in-
creased duration of induction is why sevoflurane is
contraindicated for a rapid induction-intubation se-
quence. The risks of awareness and of increased
arterial or intraocular pressure with a thiopental
Drugs 2007; 67 (5)
Drug Choice for Anaesthesia Induction
sodium-suxamethonium chloride combination are
reasons for preferring propofol to thiopental sodium
for crash induction. However, there are pharmacoki-
netic arguments that favour thiopental sodium over
propofol, chiefly in pregnant women. The duration
of an adequate depth of anaesthesia is longer with
propofol than after equipotent doses of thiopental
sodium. The risk of awareness during tracheal intu-
bation is more likely with thiopental sodium than
propofol. This may explain why thiopental sodium
is used less and less, while propofol is used more
and more. With sevoflurane, the risk of awareness is
low, owing to its continuous inhalation mode of
administration and the ability to monitor its end-
tidal concentrations. Such an argument also supports
the use of TCI with propofol.
In choosing a drug for the induction of anaesthe-
sia, the practitioner should aim to limit some of the
other adverse effects that the patient fears the most.
PONV is one of the fears most often cited by pa-
tients. Propofol may thus be chosen. However, pro-
pofol only reduces the risk of this effect following
short-lasting anaesthesia. When anaesthesia is pro-
longed and maintained with volatile agents, the fa-
vourable effect of propofol disappears.
Finally, cost remains, at the institutional level, an
influential factor in the choice of a anaesthetic agent
for induction of anaesthesia, as long as the quality
and the safety of anaesthesia remain the same. The
acquisition cost of drugs is undoubtedly lower with
the older drugs, and the cost of induction with
sevoflurane may be lower than that of propofol
under specific conditions. However, this may not
persist with the introduction of generic versions of
propofol and sevoflurane.
Acknowledgements
We would especially like to thank Mrs Claire Paillier for
her help reviewing the use of English in this review. No
sources of funding were used to assist in the preparation of
this review. The authors have no conflicts of interest that are
directly relevant to the content of this review.
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Correspondence: Professor Nathalie Nathan, Department of
Anaesthesia and Intensive Care, CHU Dupuytren, 2 Ave-
nue Martin Luther King, 87042 Limoges Cédex, France.
E-mail: nathan@unilim.fr
Drugs 2007; 67 (5)