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REVIEW

Inhalation anesthetics: a review

G. TORRI
Department of Anesthesiology, S. Raffaele University, Milan, Italy

ABSTRACT
Inhalation agents represent a basic drug used in modern balanced anesthesia. In the present review, the pharmacokinetics, effectiveness and clinical effects of inhalation agents on different systems are discussed. Data concerning the metabolism and related toxicity of halogenated agents is reviewed, with particular regard to the problem of chronic exposure
to traces of anesthetic gases in the operating room. The cardioprotective effect of halogenated agents and the actual role
of nitrous oxide and xenon are discussed. The different mechanisms of action of the inhalation agents and the evolution from a unitary theory of inhaled anesthetics to a multiple mechanism concept are presented.
(Minerva Anestesiol 2010;76:215-28)
Key words: Anesthetics, inhalation - Pharmacokinetics - Anesthetics.

he demonstration of the anesthetic properties of diethyl ether by William Morton in

1846 was one of the most significant discoveries in
medical science. Thereafter, many other anesthetics, including nitrous oxide, chloroform, ethylene, cyclopropane, trichloroethylene and divinyl
ether were introduced into clinical practice.
Unfortunately, some of these anesthetics were
explosive or toxic and have since been discontinued for clinical use.
In the 1950s, fluroxene, the first fluorinated
agent, was tested in clinical trials; however, the
drug was withdrawn in 1974 when toxic effects
were observed.1
In 1957, halothane, a halogenated hydrocarbon, was tested in clinical practice and successfully applied for surgical anesthesia.2 In 1960, a new
halogenated ether, methoxyflurane, was discovered, but its clinical application lasted a very short
time. Prolonged methoxyflurane anesthesia was
frequently associated with nephrotoxicity due to
inorganic fluoride production from its biodegradation. Simultaneously, rare cases of fatal hepatitis caused by halothane focused the search on a

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safer inhalation anesthetic. Enflurane was synthesized in 1963, while its isomer isoflurane was synthesized in 1965. The clinical introduction of
isoflurane was delayed due to its very difficult
chemical synthesis. Enflurane was introduced in
clinical practice; however, several years later, when
isoflurane was approved for clinical use, this agent
was preferred given its lower solubility and higher potency.
Sevoflurane and desflurane were developed in
the late 1960s and tested in clinical practice much
later. Sevoflurane was not immediately introduced
to the USA because of its fluorine release and its
reaction with absorbed carbon dioxide. A large
clinical trial of sevoflurane was performed in Japan,
where this agent was approved for clinical use only
in the 1990s.3 In 1995, sevoflurane was approved
in the USA for clinical use. After several years of
clinical application, no renal failure was observed,
and appropriate studies on compound A did not
show any renal effects in humans.
Desflurane is largely appreciated for its high
stability. Less than 0.02% of desflurane is metabolized, thus, plasma fluorine levels are very low.

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TABLE I. Preoperative status and risk factors of 132 patients undergoing reoperative CABG off pump (OP) or with cardiopulmonary bypass (CPB).

Formula
Molecular
weight
Boiling
point
C (at 760
mmHg)
Liquid
density
(g/mL)
(25 C/4 C)
Vapor
pressure
(mmHg at
24/25 C)
(mmHg at
20 C)
Blood/gas
partition
coefficient

Halothane

Enflurane

Isoflurane

Desflurane

C2HCIBrF3
197.54

CF2H-O-CF2CClFH
184.54

CF2H-O-CClH-CF3
184.5

CF2H-O-CFH-CF3
168.04

49-51

56.54

48.5

22.84

58.64

1.86

1.52

1.50

1.53

2884,3

2184,3

295,3

79844

197,3

44.84

2434,3

1754,3

238,3

66944

157,3

39.84

2.35

1.91

1.44

0.42

0.63

0.47

1.50

The very low solubility of desflurane allows for a

surprisingly rapid emergence from anesthesia.
Today, nitrous oxide has a controversial role in
anesthesia, and its contribution to modern balanced anesthesia will be discussed later on.
All halogenated anesthetics are very powerful.
Their therapeutic index ranges from two to four,
and their use requires knowledge of their physico-chemical properties, pharmacokinetics and
pharmacological effects on different system to prevent side effects.
Chemical and physical properties
The structure of inhalation anesthetics and their
physico-chemical properties are shown in Table I.
With the exception of desflurane, the partial
pressure of isoflurane and sevoflurane at ambient
temperatures is sufficient to obtain an adequate
concentration for clinical use with conventional
by-pass vaporizers. The high partial pressure of
desflurane (700 mmHg at ambient temperature)
requires the development of a particular vaporizer. In this vaporizer, desflurane is heated in the
sump to obtain a vapor pressure of 1400 mmHg.

216

Sevoflurane

Nitrous
oxide

(CF3)2CHF-O-CH2F N2O
200.05
44.02
-88.54-

Desflurane vapor flows from the heated sump in

parallel to the fresh gas line through two variable
resistances. One resistance is controlled by the dial
setting, while the second resistance is controlled
by a differential transducer that regulates the pressures of both desflurane and fresh gas flow.
Nitrous oxide at ambient pressures and temperatures exists in a gaseous phase and can be delivered through a flow meter.
In Table I, the solubility of inhalation anesthetics is represented by the blood/gas partition
coefficient (), i.e., the ratio of the concentrations of two phases (blood and gas) when their
partial pressures are in equilibrium. At the same
alveolar concentration, the higher the blood/gas
partition coefficient, the higher the anesthetic
concentration in the blood. The solubility of an
anesthetic in tissue differs from its solubility in the
blood, which is due to their lipid affinity. All
inhalation anesthetics are very soluble in fatty
tissues and less soluble in other tissues. Solubility
in the blood increases as body temperature
decreases, while hemodilution reduces blood solubility.4 Solubility plays a fundamental role in
the kinetics of the agents.

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N2O

Desflurane

0.8

Sevoflurane

N2O
Halothane

0.1

Isoflurane

Isoflurane

Halothane

FA/FA0

FA/FI

0.6

0.4
0.01
Sevoflurane
Desflurane

0.2

MeanSD
0.001

0
0

10
20
Minutes of administration

30

60
Minutes of elimination

120

Figure 1.Uptake and elimination of inhaled anesthetics. From Yasuda et al.6 Courtesy of the Editor.

Uptake, distribution and elimination

Factors contributing to the uptake, distribution and elimination of inhaled anesthetics have
been extensively studied and described by Eger.5
This complex process has been investigated using
mathematical, electrical analogues or by computer simulation. The different models of uptake and
distribution include tissues with different capacity (volume x tissue/blood) and with different regional blood flow.
These models, although not perfect, allow clinicians to predict the effects of changes in physiological parameters or the physico-chemical properties of the anesthetic on uptake, distribution and
elimination of these drugs.
In humans, the ratio between the alveolar and
inspired concentration (FA/FI) is used to represent the equilibrium between body tissues and
inspired concentration. The rate of rise of FA/FI
depends on many factors: the blood and tissue solubility of the anesthetic, the functional residual
capacity, alveolar ventilation, cardiac output,
regional blood flows and tissue capacity. When all

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physiological parameters are constant the increase

in FA/FI depends on the solubility of the anesthetic. The lower the anesthetic solubility the faster
the equilibration between FA and FI.
Figure 1 shows the wash-in and wash-out curves
of different anesthetics.6 Nitrous oxide, with a
greater solubility than desflurane, has more rapid
kinetics than desflurane. This effect depends on
the inspired concentration of nitrous oxide (70%)
versus 2% of desflurane. A high inspired concentration determines a faster increase in alveolar concentration, which is defined as a concentration
effect.7 FA/FI increases more rapidly when ventilation is increased with the most soluble anesthetics, while this effect is limited for low solubility agents. An increase in cardiac output reduces the
rate of rise of FA/FI of high solubility agents.5
In obese patients, the wash-in and wash-out
curves are faster with sevoflurane than with isoflurane.8 However, in obese patients, these kinetics are
slightly affected by low solubility agents, such as
desflurane or sevoflurane, when compared to normal patients.9 On the contrary, in obese patients,
anesthetic uptake is increased. Consequently, to

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maintain a constant end-tidal concentration of

anesthetic, the inspired concentration must be
increased.9
In normal subjects, the uptake of inhaled anesthetics is very high in the first minutes and declines
rapidly afterwards; after 20 minutes, as tissues with
low capacity and high flow rate reach the equilibrium, the uptake may be considered constant.10
Elimination of inhaled anesthetics from the
body is usually defined by the decrease in alveolar
concentration relative to the last alveolar concentration determined at the end of anesthesia
(FA/FAo) (Figure 1). The lower the anesthetic solubility, the faster the decrease in FA/FAo and the
shorter the recovery time. Desflurane elimination
and recovery time are more rapid when compared
to other inhalation agents. Prolonged anesthesia
(eight hours or more) increases the recovery time
from very soluble agents, an effect that is limited
for low solubility anesthetics, particularly for desflurane.11
The elimination of inhalation anesthetics may
also be expressed by their pulmonary clearance.12
This parameter represents the amount of mixedvenous blood cleared by the anesthetic in one
minute. The pulmonary clearance depends on
alveolar ventilation, cardiac output and blood
solubility. At normal values of alveolar ventilation and cardiac output, the pulmonary clearance of desflurane, nitrous oxide, sevoflurane and
isoflurane are 3.5, 3.1, 2.8 and 1.8 L/min, respectively.
During clinical anesthesia, the rate at which the
inspired anesthetic concentration rises towards the
concentration delivered by the vaporizer is dependent on the breathing system and on the amount of
fresh gas flowing into the system. When the patient
breathes in a non-rebreathing system, the inspired
concentration is constant, and the rate of rise of the
anesthetic alveolar concentration is more rapid
than it would be in a circular system. During anesthetic uptake in a circular system, the inspired
concentration of anesthetic is less than that delivered from the vaporizer. In the first phase of anesthesia, when the anesthetic uptake is very high,
the slow increase in FA/FI should be compensated for by an increase in the delivered anesthetic
concentration and fresh gas flow, as proposed by
Hendrickx 13, with simple methods.

218

Anesthetic potency
In 1965, Eger et al.14 introduced the concept of
anesthetic equipotency, which was defined as the
minimum alveolar concentration of anesthetic
(MAC) preventing movement to surgical stimulation in 50% of subjects. In all studies concerning the
determination of MAC, the alveolar concentration
was held constant for at least 15 minutes before surgical stimulation to obtain an equilibrium between
alveolar and brain partial pressure. The MAC values are shown in Table II. MAC for nitrous oxide is
104%, a value which was determined in hyperbaric conditions.15 Since its introduction from the
experimental arena, MAC has been used in many
clinical studies to compare the effects of different
inhaled agents on physiological parameters.
Of the factors that may affect the value of MAC
(e.g., hypothermia, extreme hypoxia, acidosis,
hypotension and pregnancy), opioids and patient
age play a relevant role.18, 31, 32 Benzodiazepines
and barbiturates result in a limited reduction of
MAC. Acute alcohol intoxication reduces MAC,
whereas chronic intake of alcohol or sedatives
increases MAC.33 For a large number of inhalation agents, their association with nitrous oxide
is additive,34, 35 i.e., the reduction of halogenated
MAC approximately corresponds to the inspired
fraction of nitrous oxide.
From the clinical introduction of neuromuscular blocking agents and intravenous opioids, the
clinical signs of general anesthesia were unreliable
in assessing the level of anesthesia. For this reason,
MAC was regarded as a possible approach for determining the level of surgical anesthesia. Consequently,
different types of MAC were proposed.
Because MAC represents the end tidal concentration of anesthetic determining immobility to
surgical stimulation in only 50% of patients, de
Jong and Eger 36 proposed an Extended MAC (i.e.,
MAC 95%) that approximately corresponds to
1.3 MAC (Table II).
MAC awake (MACaw) 37 represents the minimum alveolar concentration of inhalation agent
that inhibits responses to verbal command in 50%
of patients.
MAC-BAR, which was proposed by Roizen et
al.,28 represents the minimum alveolar concentration of anesthetic required to block the autonomic response to surgical stimulation in 50% or 95%

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TABLE II.Different MAC values determined in oxygen. The MAC BAR values have been determined in oxygen/nitrous oxide
mixture.
Nitrous oxide

MAC50
MAC awake
MAC95
MACEI (50)
MAC-BAR(50)

104 15
64 21

Halothane

0.78
0.41
0.90
1.46
1.45

Enflurane

16
20
24
25
28

of patients. Its value is higher than the MACaw

and MAC, allowing for control of memory, movements and autonomic responses.
The alveolar concentration corresponding to
MAC-BAR50 and particularly MAC BAR95 may
determine severe cardiovascular depression in
patients. For this reason, anesthesia is usually
obtained by combining halogenated agents with
opioids or nitrous oxide in clinical practice.
In 1999, Katoh et al.18 studied the effects of
nitrous oxide and fentanyl on different values of
MAC, and the results are shown in Figure 2. The
results of this study can be summarized as follows:
1. all points of each relationship shown in Figure
2 are equivalent in terms of anesthetic potency,
and values of MAC or MAC-BAR may be
obtained by different combinations of end-tidal
anesthetic and plasma fentanyl concentrations;
2. both nitrous oxide and fentanyl may reduce
the values of MAC and MAC-BAR; consequently, both drugs may reduce the halogenated agent
requirement. A similar effect has been obtained
with remifentanil in humans;38
3. fentanyl has limited effects in reducing the
MACaw; consequently, when high opioids concentrations are associated with a low halogenated
agent concentration, awareness may occur.
This study suggests that anesthesia may be
obtained by combining halogenated agents and
opioids (with or without nitrous oxide) in different proportions to minimize side effects of each
drug. However, the alveolar concentration of
inhaled agents must be higher than MACaw to
suppress recall of emotionally-laden information
during anesthesia.39
Effect on central nervous system
Inhaled anesthetics modify electrical activity of
the central nervous system, as measured by an

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1.68

17

1.88 24
3.23 26
1.60 28

Isoflurane

1.14
0.49
1.63

30
21
24

, 391.48 29, 39

Sevoflurane

2.05
0.62

18
22

3.35 27
2.52 18

Desflurane

6.0 19
2.42 23
7.8 29

EEG. During light anesthesia, the voltage of the

EEG increases, and its frequency decreases. As the
anesthetic concentration increases and anesthesia
level becomes deeper, the EEG activity decreases.
Desflurane and isoflurane do not produce epileptic activity, while enflurane may increase epileptic
waves.40 Data concerning sevoflurane remain controversial. Convulsions in patients with intractable
epilepsy may be suppressed by isoflurane and
sevoflurane.41
In normal subjects, cerebral flow is auto-regulated and coupled to cerebral metabolic rate. All
inhalation agents decrease cerebral metabolic rate
and oxygen consumption. The extent to which
flow and metabolism are altered depends on the
specific properties of the selected agent. In fact,
the resulting cerebral blood flow depends on two
factors, the vasoconstriction determined by metabolic suppression and the direct vasodilation determined by the anesthetic.
The inhalation agents also partially uncouple
the reactivity of cerebral blood flow to CO2. At
clinical concentrations, desflurane and isoflurane
preserve the reactivity of cerebral circulation to
changes in CO2 and flow-metabolism coupling.42
Summors et al.43 showed that sevoflurane preserves
the auto-regulation of cerebral blood flow when the
anesthetic concentration does not exceed 1.5
MAC.
The vasodilation of cerebral vessels caused by
these anesthetic agents has the potential to raise
intracranial pressure. Fraga et al.44 reported that
there was no increase in intracranial pressure for
isoflurane or desflurane in normocapnic patients.
A similar result was obtained by Artru et al.45 for
sevoflurane.
A particular effect of some inhalation agents is
the presence of excitatory effects at emergence. In
preschool children, during emergence from anesthesia, agitation has been reported to occur at high-

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Sevofluraneconcentration (%)

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Cardiovascular effects

4.5
4
3.5
3
2.5
2
1.5
1
0.5
0

MAC-BAR
MAC
MAC-awake
MAC-BAR in N2O

2
4
6
8
Fenantyl concentration (ng/mL)

10

Figure 2.Reduction of MAC, MACawake and MAC BAR by

increasing plasma concentrations of fentanyl. From Katoh et
al.18 Courtesy of the Editor.

er frequencies after sevoflurane or desflurane anesthesia when compared to halothane.46

At present, the role of inhalation agents in neuroprotection represents a new area for further investigations.
Effects on respiratory system
All potent halogenated agents depress ventilation by reducing tidal volume. The concomitant
increase in the respiratory rate does not compensate for the reduced alveolar ventilation, as it primarily determines increased dead space ventilation. Consequently, PaCO2 increases. All inhalation agents raise the threshold of the respiratory
centers to CO2, while simultaneously decreasing
ventilatory responses to CO2.47, 48
Conflicting data from different animal experiments do not allow for the determination of the
clinical relevance of the effects of inhaled anesthetic on hypoxic pulmonary vasoconstriction.
The decrease in this reflex has a minimal effect on
oxygenation during one lung anesthesia.49
Halothane, isoflurane and particularly sevoflurane decrease airway resistance, while desflurane
does not produce any change in bronchial tone.50
Halothane and sevoflurane have a minimally irritating effect on airways at clinical concentrations
and may be used for induction of anesthesia both
in children and adults.
Desflurane may act as an irritant during induction at high inspired concentrations, but has little
effect during the maintenance of anesthesia.

220

From experimental studies in healthy subjects,51, 52

the cardiovascular effects of inhaled anesthetics may
be summarized as follows. All halogenated agents
reduce the mean arterial pressure and cardiac output index in a dose-related manner. The reduction
in mean arterial pressure determined by desflurane,
sevoflurane and isoflurane is primarily determined
by the reduction in systemic vascular resistances.
On the contrary, halothane reduces the mean arterial pressure by reducing cardiac output without
reducing systemic vascular resistance. As anesthetic concentrations of desflurane and isoflurane
increase, heart rate increases; with increasing
halothane concentrations, heart rate remains nearly constant. An increase in heart rate is observed
with sevoflurane at alveolar concentrations above
1 MAC. All inhalation agents produce a dosedependent reduction in the cardiac index that may
be partially compensated by an increase in heart
rate during desflurane and sevoflurane anesthesia.
The anesthesiologist must be aware of the effects
of these particular agents on cardiovascular parameters. Patients responses to inhalation agents may
be modified by cardiac diseases, surgical stimulation and many drugs. In some studies, desflurane
and sevoflurane showed high cardiovascular stability both in young and old patients.53, 54
The myocardial depression and reduction in
mean arterial pressure produced by halogenated
agents is slightly increased when these agents are
combined with nitrous oxide.
The mechanism of arrhythmia induction during
administration of potent halogenated anesthetics is
not completely understood. Sevoflurane may prolong
the QT interval and should be administered with
caution in patients with idiopathic or acquired long
QT intervals.55 Sevoflurane and isoflurane may suppress arrhythmias caused by local anesthetics.56.
The threshold of epinephrine for ventricular
arrhythmia is higher for desflurane and sevoflurane when compared to halothane or isoflurane,
and the arrhythmogenic effects are very low with
these two agents.57, 58
Regional blood flows
Coronary blood flow is auto-regulated and
depends primarily on myocardial demand. Some

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studies in animals have demonstrated that auto-regulation is preserved during exposure to clinical
concentrations of halogenated anesthetics. In an
animal model, isoflurane may result in coronary
steal, a diversion of blood flow arising from a
fixed stenosis.59 This effect has not been confirmed
in humans. Sevoflurane and desflurane do not
cause coronary steal.
The effects of inhalation agents on cerebral
blood flow have been previously discussed.
Many inhalation anesthetics decrease portal
venous flow, while halothane decreases hepatic
artery blood flow and oxygen delivery to the liver.60 All halogenated agents decrease renal blood
flow, glomerular filtration and urine output,
although auto-regulation of renal blood flow is
preserved.61 The decrease in renal blood flow during maintenance of anesthesia is often related to a
reduction in circulating volume caused by increased
vascular capacity.
Cardiac protection by inhaled anesthetics
Halogenated agents mimic the cardioprotective effect of ischemia first described in 1986 by
Murry,62 which represents an adaptive response
to brief sublethal episodes of ischemia leading to
protection against subsequent lethal ischemia.
Two windows of cardioprotection have been
described: an early phase lasting two hours and a
late preconditioning phase reappearing 24 hours
in the postoperative period and lasting 72 hours.63
The mechanism of cardioprotection is very complex. It includes intracellular reactions involving
membrane Gi protein-coupled receptors, phospholipase , diglycerol and protein kinase C, causing activation of the KATP channels of both the
mitochondria and sarcolemma. Reactive oxygen
species (ROS) also appear to play an important
role.64, 65 Moderate ROS production induced by
inhaled anesthetics is required to induce preconditioning, which in turn, allows for a reduction
in the ROS excess seen during reperfusion.
Inhaled anesthetics also reduce platelet adhesion to the vascular wall, while not impacting
endothelial cell activation.66
Many clinical studies have confirmed the cardiac
preconditioning effects of inhaled anesthetics in
patients undergoing cardiac surgery,67-71 and a
recent meta-analysis pooling data from studies

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exploring the effects of desflurane and sevoflurane

found a significant reduction in myocardial infarction, ICU stay, time on mechanical ventilation in
the ICU, hospital stay, in-hospital mortality and
incidence of long term events.72
The cardioprotective effect of halogenated agents
in patients with coronary artery disease who are
undergoing non-cardiac surgery has not yet been
supported by clinical trials.
Effects on muscle-relaxation
Inhaled anesthetics cause an enhancement of
the effects of neuromuscular blocking drugs and,
consequently, reduce the muscle relaxants requirement.
All halogenated agents may trigger malignant
hyperthermia (MH), a very rare adverse event of
general anesthesia. Nevertheless, cases of MH or
delayed MH have been reported both for desflurane and sevoflurane.73-75 However, the incidence
of MH seems to be much lower with desflurane
and sevoflurane than with halothane, particularly when it is administered in association with succinylcholine.
Metabolism and toxicity related to inhalation
agents
Recently, interest around the metabolism of
inhaled agents has been focused on the toxicity of
its metabolites, which may be harmful for patients.
Halothane is largely metabolized to fluoride,
80% of which is found in the urine as hexafluoroiodopropanol; this compound does not undergo further biodegradation but is instead conjugated to glucoronide. In patients who develop
halothane hepatitis, a reactive metabolite of
halothane is thought to acetylate liver proteins,
which can modify these proteins, making them
neoantigens. It is the antibodies that are formed
against neoantigens that result in liver injury.76
Fatal halothane hepatitis is estimated to occur in
1 every 100,000 anesthesia procedures.
The extent of enflurane metabolism is approximately 2%, and the majority of the anesthetic is
eliminated through the lungs. Enflurane is metabolized in the liver by the cytochrome P450
enzymes. The final products of its metabolism

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include difluoromethoxydifluoroacetic acid and

fluoride. The possible nephrotoxicity of enflurane
is a concern only when high inspired concentrations of the drug are used or after prolonged anesthetic procedures.
Isoflurane undergoes minimal oxidative metabolism to inorganic trifluoroacetic acid and fluoride and involves the cytochrome P450 2EI
enzyme.
Desflurane is very resistant to metabolism, as
only 0.02% of the drug is metabolized. Its biotransformation is very similar to isoflurane.
Desflurane is unlikely to result in formation of
neoantigens from oxidative metabolism. Serum
fluoride has not been observed in humans after
exposure to high desflurane concentrations or prolonged anesthesia.77
Sevoflurane is subjected to cytochrome P450
2EI oxidative degradation, and the final metabolic products are carbon dioxide, inorganic fluoride
and hexafluoroisopropanol. Fluoride-induced
nephrotoxicity after sevoflurane administration
has been extensively investigated. The relative
paucity of renal sevoflurane defluorination may
explain the absence of the clinical nephrotoxicity
of this agent, despite the fact that plasma fluoride
concentrations may in some cases approach 50
mol/L.78 Kharasch et al. found that there is no
significant difference in renal tubular function and
cell integrity between the renal effect of sevoflurane
and isoflurane in surgical patients undergoing lowflow anesthesia for as long as seven hours.79
Prolonged anesthesia with sevoflurane does not
impair renal concentrating functions, as demonstrated by a study based on the desmopressin test.80
Degradation in CO2 absorbents
All halogenated agents degrade in the presence
of dry alkaline CO2 absorbents. The degradation
of sevoflurane to compound A depends on the
temperature and water content in the absorber.81
Compound A has been shown to cause renal
injuries in rats when inhaled at high inspired concentrations. Compound A is less toxic in humans
because the activity of the -liase enzyme is much
lower in humans than in rats.82 When a fresh gas
flow of 2 L/min is given, compound A concentration in the circuit is very low, and renal toxicity has never been reported.

222

In dry CO2 soda lime or Baralyme, desflurane,

enflurane and isoflurane degrade to carbon monoxide (CO).83 Carbon monoxide may result from
the biodegradation of these anesthetics because a
particular moiety (CF2H-) is present in their molecules. Sevoflurane and halothane do not possess
this moiety and do not degrade to CO.
In new absorbents, the elimination of monovalent bases prevents both compound A and CO
production; this is also the case when these new
absorbents are dry.84
Long term exposure to trace of anesthetic.
At the beginning of the 1960s, some studies
demonstrated that in the operating room, without adequate climate control and without a waste
gas scavenging system, occupational exposure to
anesthetic gases exceeded the threshold limits. A
study by Veisman 85 suggested that long term exposure to traces of nitrous oxide could contribute to
the increased incidence of abortion and congenital abnormalities in female anesthesiologists.
Consequently, exposures to trace inhaled anesthetics have been thought by many anesthesiologists to cause adverse effects on operating room
personnel.
The majority of the following epidemiological
studies on occupational hazard have been focused
on miscarriage, birth defects, teratogenicity, carcinogenicity and neurobehavioral functioning.
These studies have been used in a meta-analysis
by Buring et al.86 that showed somewhat of an
increase in the relative risk for liver or kidney diseases and for cervical cancer in woman. In a second meta-analysis, Bovin 87 found a borderline
increase in the relative risk of spontaneous abortion
in female anesthesiologists, while in the subgroup
exposed to nitrous oxide, the relative risk of abortion was not increased.
However, the studies used in the two metaanalyses have been heavily criticized for loading
of the questionnaires, lack of information on exposure time and anesthetic levels, poor response rates
to questionnaires and selection bias.88 Further
studies failed to demonstrate an increased rate of
cervical cancer or other diseases.89
Two studies by Ericson and Kallen,90, 91 based on
the registered data of operating room personnel
showed no association between occupational expo-

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sure and reproductive effects. A prospective study

among female anesthesiologists and other doctors
was conducted by Spence.92, 93 This study concluded that there is no evidence to suggest that
exposure to traces of waste anesthetic gases results
in adverse health consequences. The results also
indicated that female anesthesiologists did not
have a greater incidence of infertility than other
physicians.
Given the fact that many of the studies that
have been conducted have been retrospective studies and have had many methodological errors, the
evidence for an association between anesthetic
exposure and congenital abnormality seems to be
inconsistent and unrelated to hours of exposure
to trace of anesthetics.
Because the possible effects of health hazards
from long-term exposure to traces of inhalation
agents cannot yet be excluded, many authorities in
different countries have established limits for exposure to inhalation anesthetics. These limits range
from two to ten ppm as a time-weighted average
concentration over the time of exposure for halogenated agents and 50-100 ppm for nitrous oxide.
The reduction in operating room pollution
should be a high priority. For this reason, the ASA
Committee on the Occupational Health of
Operating Room Personnel has offered recommendations to minimize exposure levels. These
recommendations include an efficient climate system, a waste gas scavenging system, the use of low
flow ventilation technique and correct technique
of anesthesiologist.
Should we continue to use nitrous oxide ?
For one and a half centuries, nitrous oxide has
played a relevant role in general anesthesia; however, in the last decade, some critical reports on
nitrous oxide have been published.94-99
Many of the side effects of nitrous oxide correlate with its physical properties. Its ability to diffuse into air filled cavities increases the likelihood
of pneumothorax, air emboli and pressure in the
cuff of the endotracheal tube. Nitrous oxide diffusion causes an increase in middle ear pressure and
distension of the bowel, possibly resulting in
increases in postoperative nausea and vomiting
According to Neuman,100 during laparoscopic

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abdominal surgery, nitrous oxide in combination

with methane or hydrogen contained in the bowel could cause combustion.
The biological effects of nitrous oxide have been
recently reviewed by Sanders et al.101
Nitrous oxide inactivates vitamin B12 by an
irreversible oxidation of the central cobalt and
depresses methionine synthetase activity in both
animals and humans.102 Recent data show that in
patients with a homozygous mutation, nitrous
oxide anesthesia results an increase in plasma
homocysteine levels. The increase in plasma homocysteine level could increase perioperative myocardial complications 103, however, no clinical data
are available to support this hypothesis. An international study involving a large number of patients
at risk of coronary artery disease (Enigma II) will
probably ascertain the benefits and risks of removing nitrous oxide from the anesthetic technique.104
The results from a questionnaire proposed by
the Association of Anesthetists of Great Britain
and Ireland indicate that 49% of anesthetists had
reduced their use of nitrous oxide. This was due to
medical considerations rather than concerns over
health and pollution.105
According to Baum,106 nitrous oxide should not
be used routinely as a carrier gas, and the safer
mixture of oxygen/medical air is able to replace
this old anesthetic with some economical advantages.
The combination of halogenated agents with
short acting opioids results in the possibility of
limiting the clinical application of nitrous oxide.
The advantages of nitrous oxide include its analgesic properties, which allow for the reduction of
halogenated agents and may limit their cardiorespiratory effects in critically ill patients. A recent
paper suggests that nitrous oxide prevents the
enhancement of pain sensitivity induced by nociceptive inputs and by acute fentanyl and morphine tolerance.107 Consequently, whether the side
effects of nitrous oxide support its exclusion from
clinical practice remains controversial.
The interest in the continued use of nitrous
oxide can be found in intravenous sedation to
reduce the risk of awareness and recall or in some
critical situations when administration of halogenated agents must be rapidly interrupted.
Attempts to replace nitrous oxide with other

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gases had led to an increase in studies on xenon.

This inert gas does not undergo metabolic biotransformation and has no direct negative environmental effects. Xenon has a very low solubility in the blood (=0.15), and its potency is higher when compared to nitrous oxide blood solubility (MAC 63% vs. 105%).108
Xenon cannot be synthesized, and the available
amount is very low. Consequently, at present, the
cost of the compound may be a limiting factor for
clinical use. All methods proposed for the use of
xenon in a totally closed system, with recycling of
the waste gas, are very sophisticated and require a
high technology anesthesia workstation. Therefore,
this gas should be of great interest in our field as
a possible alternative to nitrous oxide for particular surgical procedures.
Where and how inhalation agents act?
The mechanism of general anesthesia has been
presented in two excellent reviews and is here summarized.109, 110
Over the last decades, our understanding of the
mechanism of general anesthesia has rapidly
evolved. Overton and Mayer 111, 112 independently observed a strong correlation between inhalation anesthetic potency and their solubility in olive
oil. This correlation suggested that the site of action
of these agents could be the lipids of the cell membrane. The lipid theory proposed in the 19th
century persisted until the late 1970s when new
research introduced the hypothesis that proteins
could be directly involved in the mechanism of
general anesthesia. Franks and Lieb 113, 114 demonstrated that protein may be a site of action for
inhalation agents; in these studies, inhalation agents
inhibited a lipid-free preparation of the enzyme
firefly luciferase.
In the last year, particular attention has been
given to ion channels. Ion channels are specific
proteins that regulate the flow of ions across the cell
membrane and act as mediators of neural activity.
Binding sites for anesthetics have been identified in different ion channels, including serotonin
receptors, nicotinic acetylcholine receptors, aminobutyric acid type A (GABAA) receptors,
glycine receptors and glutamate receptors activated by N-methyl-D-aspartate (NMDA) or alpha-

224

amino-3-hydroxy-methyl-4-isoxazolepropionic
acid (AMPA).115, 116 Inhalation agents prolong
inhibitory postsynaptic channel activity of GABAA
and glycine receptors and inhibit excitatory synaptic channel activity (nicotinic acetylcholine, serotonin and glutamate receptors). Although there is
strong evidence that anesthetics may act on GABAA
receptors, xenon and nitrous oxide only minimally enhance the activity of these receptors.117
Inhalation agents prevent movements in
response to surgical noxious stimulation by depressing spinal cord function. The evidence for this
comes from experiments in decerebrate rats and
goats by Rampil et al.118 and Antognini and
Schwartz.119 This study demonstrated that MAC
measures the effect of inhalation agents on the
spinal cord rather than in the brain.
At the level of spinal motor-neurons, inhalation agents increase the activity of inhibitory
glycine receptors and inhibit post-synaptic AMPA
and NMDA receptors independent of their action
on GABAA receptors.120 Sonner et al. hypothesized that GABAA receptors are not involved in
mediating immobility.121 According to other
sources, inhalation agents determine a contribution
of GABAA receptors to immobility.122
Inhalation agents decrease the transmission of
noxious stimulation ascending from the spinal
cord to the brain and affect their action in the
brain.123
The amnesic effect of anesthetic agents is mediated within particular regions of the brain. At low
concentrations, inhalation agents inhibit nicotinic
acetylcholine receptors and impair memory and
learning, but not immobility.124 The susceptibility of neurocortical neurons to inhalation anesthetics at concentration equivalent to MACawake
significantly increases the GABAAergic synaptic
inhibition.125
These data suggest that anesthetics induce amnesia and immobility by affecting different sites.
Using brain imaging (positron emission tomography and functional magnetic resonance imaging) Alkire et al. found a decrease in glucose metabolic activity produced by inhalation agents, which
reflects a reduction in synaptic activity.126, 127 The
thalamus and midbrain reticular formation are
more depressed by inhalation agents than other
regions of the brain. Some regions of the brain dif-

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fered in their activity between the awake state and

the anesthetic state.
Another study of Alkire et al. shows a significant correlation between the regional metabolic
reductions that occur during isoflurane anesthesia
in humans and the regional distribution of muscarinic (acetylcholine) receptors.128
In conclusion, after the identification of many
sites of action for inhalation agents our knowledge on the mechanism of general anesthesia have
evolved from a unitary hypothesis to the more
recent concept of complex effects and multiple
mechanisms. Despite the development of new
techniques and the increased interest in understanding this area, the exact mechanism of anesthetic action remains a complex and unresolved
problem.

5. Eger EI. Anesthetic uptake and action. Baltimore, MD: The

Williams and Wilkins Co.; 1974.
6. Yasuda N, Lockhart SH, Eger EI II, Weiskopf RB, Lin J.
Comparison of kinetics of desflurane and halothane in
humans. Anesthesiology 1991;72:316-24.
7. Epstein RM, Rackow H, Salanitre E, Wolf GL. Influence of
the concentration effect on the uptake of gas mixtures: the
second gas effect. Anesthesiology 1964;25:364-71.
8. Torri G, Casati A, Comotti L, Bignami E, Santorsola R,
Scarioni M. Wash-in and wash-out curves of sevoflurane and
isoflurane in morbidity obese patients. Minerva Anestesiol
2002;68:523-7.
9. Lemmens HJM, Saidman LJ, Eger EI II, Laster MJ. Obesity
modestly affects inhaled anesthetic kinetics in humans. Anesth
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MG et al. Effect of anesthetic duration of kinetic and recovery characteristics of desflurane vs desflurane in volunteers.
Anesth Analg 1998;86:414-21.
7. E

Conclusions
The pharmacokinetic advantages of inhalation
anesthetics are unique. By increasing or decreasing
their inspired concentration, it is possible to
increase or decrease their concentration in the
blood and tissues, allowing for rapid changes in
anesthesia depth and providing a simple method
for inducing, maintaining and reversing general
anesthesia. The early pioneers of anesthesia were
aware of these advantages, and today, the monitors included in modern anesthesia workstations
allow us to directly control the inspired and the
end-tidal concentrations of these agents. The flexibility of inhalation anesthesia cannot be reproduced with modern intravenous hypnotics or opioids, even when they are delivered by sophisticated infusion pumps. Furthermore, it is important
to underline the protective effects of inhalation
agents on several different organs, as similar effects
cannot be obtained with clinical concentrations
of hypnotics or opioids.
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Received on March 20, 2009 - Accepted for publication on October 27, 2009.
Corresponding author: G. Torri, Department of Anesthesiology, S. Raffaele University, via Olgettina 60, 20132 Milan, Italy.
E-mail: torri.giorgio@hsr.it

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March 2010