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Occupational exposure to
anaesthetic gases: a role for TIVA
Michael G Irwin, Theresa Trinh & Che-Lin Yao

University of Hong Kong, Queen Mary Hospital, Department of Anaesthesiology, Room 424,
Block K, Hong Kong

1. Development of anaesthetic
2. Effects on the environment
3. Assessment of occupational
4. Mechanisms of occupational
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5. Effects of occupational exposure

6. Potential solutions


9. Expert opinion

Modern anaesthesia is still mostly administered by the inhalational route

and there is increasing concern over its potential for pollution. One of the
first gaseous anaesthetic agents was nitrous oxide and this is still widely used
today despite being associated with adverse effects caused by depression of
vitamin B12 function and diminished reproductive health. The use of halothane
is associated with hepatitis but the adverse effects of newer halogenated
hydrocarbons are less well recognised. Chronic exposure may cause reduction
in antioxidant activity in plasma and erythrocytes, inhibition of neutrophil
apoptosis, depression of central neuro-respiratory activity, increased DNA
breaks, effects on cerebral blood circulation and altered renal function.
Inhalational anaesthetics also have adverse environmental effects, including
ozone damage and greenhouse gas effects. Levels of inhalational anaesthetics
in the ambient air of operating theatres and recovery rooms often exceed those
stated in national guidelines. Anaesthetic procedures can be modified and
air-conditioning and air scavenging systems should be used to minimise the risks
from occupational exposure and threats to the environment. Such contamination
could be avoided with the use of total intravenousanaesthesia.
Keywords: anaesthetic techniques, environmental pollution, isoflurane, nitrous oxide, propofol,
sevoflurane, total intravenous anaesthesia, volatile anaesthesia
Expert Opin. Drug Saf. (2009) 8(4):473-483

1. Development

of anaestheticgases

The state of anaesthesia is inherently dangerous and most drugs have a relatively low
therapeutic index. To reliably produce anaesthesia and safe recovery, it is important
that these drugs can be easily titrated and, therefore, have a short time to peak effect
and short duration of action. In the 19th century, the most logical and safest way to
achieve this was by administering drugs by the inhalational route. With improved
vaporiser technology and gas monitoring together with advances in inhalational
drug pharmacology, it is not surprising that this legacy persists to thisday.
Nitrous oxide was one of the first of the gaseous agents used for anaesthesia. It
was discovered in 1772 but was not introduced into usual anaesthetic practice
until 1878. The first volatile anaesthetic to be used in anaesthesia was diethyl
ether, but complications, such as emesis and flammability, led to the introduction
of chloroform. It was a great innovation but chloroform also produced toxic
effects. Although John Snow is believed to have given 4000 chloroform anaesthetics
without any deaths [1], in 1912, the American Medical Association declared its
use in minor operations to be unjustifiable due to toxicity. Trichloroethylene was
introduced in the 1930s and had many beneficial properties compared with chloroform, including reduced hepatotoxicity. It was a good anaesthetic agent but was
associated with a number of limitations and pharmaceutical grade trichloroethylene
is no longer produced. Nitrous oxide is a good analgesic as it is an N-methyl-d-aspartate
receptor antagonist and may prevent the enhancement of pain sensitivity induced
by nociceptive inputs and oppose acute morphine tolerance [2]. It is relatively easy

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Occupational exposure to anaesthetic gases: a role for TIVA

to produce and administer and is still commonly used today,

but ether is the only one of the other three agents that
remains in use in somecountries.
The next major development in gaseous anaesthesia was
the introduction of halothane. This halogenated hydrocarbon
was synthesised in 1951 and first used clinically in 1956.
Exposure to halothane is associated with a risk of severe liver
damage, the incidence of which increases with frequency and
duration of exposure [3]. Halothane is one of the ten most
common causes of fatal hepatotoxicity according to the drug
monitoring database of the WHO. During metabolism of
halothane through oxidative reactions in the liver, tissue
acetylation occurs due to the formation of reactive intermediates. Proteins modified by acetylation may constitute neoantigens with a potential for triggering an antibody-mediated
immune response [4]. On rare occasions (< 1 in 30,000 cases),
this triggers an autoimmune reaction called halothane hepatitis,
which has a mortality rate of 30 70%. Halothane can also
cause and induce malignant hyperthermia. Despite these recognised adverse effects, halothane is widely used in some countries because it is inexpensive and provides smooth induction
of anaesthesia andrecovery.
Other halogenated inhalational anaesthetics, enflurane,
isoflurane and desflurane, were developed partly with the aim
of finding volatile anaesthetics that were not metabolised to
the same extent as halothane. However, these can also produce
metabolic hepatocellular injury in humans to a variable extent
due to the production of metabolites such as triflouroacetylate,
which can act as haptens. The likelihood of suffering postoperative hepatitis depends on the amount of the anaesthetic
metabolised and is, thereby, considerably less with enflurane,
isoflurane or desflurane compared with halothane. An estimated
two patients per million will develop severe liver dysfunction
after administration of enflurane, although this agent is seldom
used in anaesthesia any more [5]. There are also a few reports
of occurrence after the use of isoflurane [6] but only three
associated with desflurane [7]. As sevoflurane does not form
triflouroacetylate liver proteins, theoretically patients sensitive
to other volatile anaesthetics could safely be anaesthetised
with sevoflurane. Despite this, there have been two recent
case reports of fatal sevoflurane-induced hepatotoxicity [8,9]. It
has been suggested that perhaps the production of compound
A can be attributed to liver toxicity as it can react with liver
proteins and transform them into antigenic materials [8].
Compound A has been shown to exhibit nephrotoxicity in
rodents but no significant changes in renal function parameters
have been reported in surgical patients [10]. Plasma inorganic
fluoride concentrations are regularly increased after sevoflurane.
Elevated inorganic fluoride concentrations have been associated
with nephrotoxicity following methoxyflurane anaesthesia but
not aftersevoflurane.
One of the first intravenous anaesthetic agents was
thiopentone, discovered in the early 1930s. Thiopentone is
an ultra short-acting barbiturate that is most commonly
used in the induction phase of general anaesthesia. It is not

used for maintenance anaesthesia because of its long,

context-sensitive half-life. Several other intravenous agents,
such as propanidid and alfaxalone, were introduced over the
years but subsequently withdrawn because of adverse effects.
Etomidate is a short-acting intravenous agent, which is still in
use for the induction of anaesthesia. It is a potent suppressant
of adrenal steroidogenesis, effectively inducing reversible
pharmacological adrenalectomy [11]. Recent evidence suggests
that for every five patients with septic shock given etomidate
without corticosteroid supplementation, one patient will die
as a consequence [12]. It is, therefore, unsuitable for maintenance
of anaesthesia and is also associated with a high incidence of
postoperative nausea andvomiting.
Propofol has become one of the most widely used anaesthetic
agents since its introduction in the 1970s. It is a short-acting
intravenous agent for the induction and maintenance of general
anaesthesia in adults and in paediatric patients older than
1 month. It is also used in the intensive care unit (ICU), for
the sedation of intubated and mechanically ventilated adults.
It seems to be safe for use in porphyria and has not been
known to trigger malignanthyperthermia.
Volatile anaesthetic agents are suitable for both the induction
and maintenance of anaesthesia. However, mask phobia, patient
preference and compliance with breathing techniques to
achieve rapid induction make these anaesthetic gases generally
less popular than intravenous agents for induction of anaesthesia. Current anaesthesia practice is usually to follow induction with an intravenous agent by maintenance anaesthesia using
a volatile anaesthetic agent, often in combination with nitrous
oxide. Nitrous oxide is also sometimes used concurrently with
intravenous maintenance anaesthesia. Despite their widespread
use, anaesthetic gases have been found to be associated with
adverse effects on the environment and also on healthcare
personnel subject to occupational exposure. At present, the
risks from long-term exposure to newer agents areuncertain.
2. Effects

on theenvironment

Until now, most reviews of the use of nitrous oxide and

volatile agents have focused on patient benefits, with little
regard to the harmful effects on both the individual and the
environment. Further consideration should be given to the local
and global environmental issues. Less than 5% of the dose of
the newer volatile anaesthetics is metabolised by the patient;
the vast majority is eliminated in patients breath. In a modern
breathing circuit, this gas is then effectively removed from
the operating room atmosphere by scavenging systems, which
vent the gases to the atmosphere [13].
Nitrous oxide is a greenhouse gas with a long lifetime and
can, therefore, contribute to global warming [14]. All volatile
anaesthetics are halogenated chlorofluorocarbons (halothane,
enflurane, isoflurane) or fluorinated hydrocarbons (sevoflurane
and desflurane) and are thus potentially damaging to the
earths ozone layer. In addition, they also contribute to global
warming. The bromide-containing agent, halothane, is the most

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Irwin, Trinh & Yao

destructive against ozone, whereas isoflurane and enflurane

(which contain only chloride and fluoride) have a lesser
impact [15]. Sevoflurane and desflurane contain neither chloride
nor bromide, and thus do not pose a threat to stratospheric
ozone and are less likely to be potential greenhouse gases [16].
The global warming potential of halogenated anaesthetics is
up to 2000 times greater than carbon dioxide. The anaesthetic
gas emissions from 1100 hospitals across Canada alone are
estimated to be equivalent to > 1.1 million tons of carbon
dioxide a year [13].
The impact of these greenhouse and ozone-depleting effects
is mitigated partly by the relatively short lifetimes of the volatile
anaesthetic gases in the atmosphere, which have been estimated
to be 2, 6 and 5years for halothane, enflurane and isoflurane,
respectively [15]. Given that it takes an average of 2 years for
these agents to reach the stratosphere and the ozone layer,
their relative contribution to the problem of ozone depletion
was considered to be small in 1990 compared with the global use
of other chlorofluorocarbons and halogenated hydrocarbons[17].
Since that time, and the introduction of the Montreal Protocol
on Substances that Deplete the Ozone Layer, the production
of many of these other chemicals hasceased.
Metabolic products of intravenous anaesthetic agents are
released into the hospitals sewage system. It is possible that
degradation products, such as phenol from propofol, are
produced, but it is not known whether there is significant
build-up in the food chain [18].
3. Assessment

of occupationalexposure

Maximum workplace concentrations of nitrous oxide, halothane,

enflurane and isoflurane have been established by national
agencies in many industrialised countries [18]. As there are no
absolute safe levels of gases, the recommended thresholds for
occupational exposure vary among countries[19]. Occupational
exposure standards limits have become increasingly strict but
are usually advisory rather than regulatory [19]. However, the
Control of Substances Hazardous to Health regulations in the
UK require employers to attempt to control the occupational
exposure of their staff and encourages an audit process to
ensure that standards are being met [19,20].
The UK, Italy, Denmark, Norway and Sweden and have set
exposure limits for nitrous oxide at 100 parts per million
(ppm) [21], whereas the National Institute for Occupational
Safety and Health (NIOSH) in the US set nitrous oxide limits of
25 ppm as an 8-h time-weighted average and a ceiling of 2 ppm
in 1h for volatile anaesthetics when used alone, and 0.5 ppm
in 1 h when used in combination with nitrous oxide [21,22].
The Netherlands also has a limit of 25 ppm for nitrous oxide
and 2 ppm for enflurane and isoflurane. The UK has a limit of
10 ppm for halothane and 50 ppm for enflurane and isoflurane.
Germany, Sweden, Norway, the Netherlands and Denmark all
have limits of 5 ppm for halothane (Table 1) [19]. Despite the
introduction of national exposure limits, published studies
demonstrate that these levels are often exceeded [23-25].

An Austrian study evaluated anaesthesiologist exposure

during four different induction techniques in which patients
were randomly assigned to one of the following: sevoflurane
and nitrous oxide from a re-breathing bag; sevoflurane and
nitrous oxide from a circle circuit; propofol 3 mg/kg; and
thiopental sodium 5 mg/kg [25]. Anaesthesia was maintained
with sevoflurane and nitrous oxide through a laryngeal mask.
During induction with sevoflurane, anaesthetic vapour concentrations in the operating room often exceeded the NIOSH
recommended exposure ceiling of 2 ppm in 1h, but remained
below 20 ppm [25]. During the maintenance phase, exposure
also frequently exceeded the 2 ppmlimit.
In Poland, where there are no regulations determining the
maximum concentrations of anaesthetic agents, levels of
nitrous oxide in the theatre atmosphere exceeded European
and North American standards. It was suggested that a lack
of appropriate technical facilities in operating rooms is aggravated by incompetence of the technical supervision staff and
negligence of the anaesthesiologic (sic) personnel [26].
Significant correlations have been shown between
environmental anaesthetic exposure and the concentration of
nitrous oxide, halothane, enflurane and isoflurane in the urine
of operating room staff [27]. Operating room staff exposed to
sevoflurane on a daily basis also exhibited significantly increased
(p < 0.05) levels of sevoflurane in exhaled air after duty,
compared with baseline values [28]. Furthermore, detectable
levels of sevoflurane were recordable the day after a shift in
the operating theatre. This implies that sevoflurane remains
in the body for a long time, leading to an extended period of
low-grade systemicexposure.
Occupational exposure to halothane and nitrous oxide
does not impact on the driving performance of long-term
operating theatre employees [29]. However, the levels of anaesthetic found in operating room personnel were sufficiently high
to affect the driving skills of volunteers. This implies that longterm employees develop tolerance to the effects of anaesthetic
gases and it is possible that employees who are new to the
operating room environment may be at risk of impaired
driving following occupationalexposure.
Some studies have shown that with modern operating
theatre air conditioning, occupational exposure to inhalational
anaesthetics is low and safe according to modern workplace
laws and healthcare regulations [30-32]. In less well-equipped
units and in non-operating theatre areas, however, the use of
these agents continues to causeconcern.
In the recovery room, anaesthetic gases are eliminated
from the patient by exhalation, thereby, releasing it into the
air. Scavenging equipment is seldom installed in the recovery
room and, consequently, there is a risk of exposure to hospital
staff caring for these patients. The problem may be worse in
non-theatre areas, as they often have inadequate ventilation
and no anaesthetic gas scavenging equipment. There is evidence
of environmental levels of volatile agents exceeding the
recommended limits in these areas [23]. A study of eight
hospitals in Wales, UK reported that many non-theatre

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Occupational exposure to anaesthetic gases: a role for TIVA

Table1. Exposure limit (ppm) for various countries.


Nitrous oxide


Other volatiles




50 (Enflurane
and Isoflurane)











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2 (Enflurane
and isoflurane)

*8-h time weightedaverage.

Ceiling in 1h when usedalone.
Ceiling in 1h when used in conjunction with nitrousoxide.
NIOSH: National Institute for Occupational Safety and Health; ppm: Parts permillion.

locations, such as delivery suites and radiology units, lacked

adequate ventilation and anaesthetic gas scavenging, resulting in
levels of nitrous oxide and halothane that exceeded set standards (Figure1) [23]. Personnel such as postoperative nurses working in non-theatre areas may, therefore, exceed recommended
limits for occupational exposure to anaesthetic gases [33].
Even in a modern working environment with low-leakage
anaesthesia machines, scavenging systems, high room ventilation
rates, no intermittent mask ventilation, low-to-medium concentrations of sevoflurane and strict control of endotracheal tube
cuff pressure, it was shown that exposure to sevoflurane and
nitrous oxide could not be kept below threshold values in all
cases [24]. In a study conducted in Germany, the 2 ppm level
for sevoflurane was not exceeded in the case of anaesthetists and
surgeons, but was exceeded in 16% of measurements from
auxiliary nurses. The level of 25 ppm nitrous oxide was
exceeded in 28% of the measurements for anaesthetists and
in 16% for surgeons and auxiliary nurses [24].
4. Mechanisms

of occupationalexposure

The anaesthetic technique used can influence the release of

anaesthetic gases. During induction of anaesthesia with volatile
anaesthetic agents, release of gas into the environment is greater
than during maintenance anaesthesia [25]. This is related to
the high concentrations of anaesthetic agent and the use of a
face mask and high fresh gas flow during induction [18].
Leakage of gas from between the mask and the patients face
results in the release of high concentrations of anaesthetic agents
into the ambient air, especially in patients with a difficult
airway or delay in intubation. During the maintenance phase,
the use of a laryngeal mask airway can markedly decrease

these losses but is associated with higher leakage rates than

tracheal tubes [30]. Additionally, during intravenous induction,
administration of the anaesthetic gas to be used for maintenance
may be initiated while the patient is being ventilated with a
face-mask. Subsequent intubation allows release of anaesthetic
gases into the operating theatre. Similarly, flushing the anaesthesia circuit on emergence to hasten recovery will also lead to
operating room contamination, as it is usually not scavenged.
Also when patients who are anaesthetised with an inhaled agent
are allowed to breathe spontaneously through a laryngeal mask
while disconnected from the circuit, the anaesthetic gases will
be exhaled into theroom.
A recent US study into the use of such anaesthetic
management techniques showed mean sevoflurane concentrations
of 6 ppm in the vicinity of the anaesthesiologists breathing
area [34]. It has been suggested that the vaporisation should
be continued but the fresh gas flow turned off during intubation, as this may reduce pollution [35]. However, the previous
study showed that switching off the vaporiser but leaving the
fresh gas flow running takes four times as long to fully eliminate the volatile agent from the circuit. For that reason, the
American Society of Anesthesiologists (ASA) recommends
that both vaporiser and fresh gas flow should be switched off
during intubation to minimise contamination [36]. However,
it must be remembered that in many modern anaesthetic
machines it is not possible to discontinue the free gas flow
function completely. A reasonable compromise in this circumstance would be maintenance of intravenous anaesthesia with
an easily titratable drug, either by repeated bolus or infusion,
until the airway is secured and the cuff fully inflated, before
commencement of inhalationanaesthesia.
In paediatric surgery, uncuffed tubes are often used for
airway management during anaesthesia in children under the
age of 8 10years, because a cuffed tube may cause pressure
lesions of the tracheal mucosa [37]. Workplace concentrations of
sevoflurane can be increased with the use of uncuffed tracheal
tubes in children and are significantly lower when cuffed tracheal
tubes are used in adults in the same operating theatre [18].
Initial mask induction followed by cuffed endotracheal intubation or intravenous induction followed by uncuffed endotracheal intubation produced significant pollution with nitrous
oxide in another paediatric study [38]. There does seem to be
some situational variability as a study comparing the laryngeal
mask airway and the uncuffed tracheal tube in paediatric
patients receiving intermittent positive pressure ventilation found
no difference in peri-operative sevoflurane concentration in a
modern operating theatre and these levels were five times
lower than occupational safety limit requirements[39]. Another
study also demonstrated a high level of safety with the use of
both cuffed and uncuffed endotracheal intubation for paediatric
surgery, as assessed by environmental and urinary sevoflurane
levels. On the other hand, the use of the laryngeal mask was
associated with an increase in these sevoflurane levels [40].
Certain circuits used in paediatrics such as the Jackson-Rees
modification of the Mapleson D have no inbuilt scavenging

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Concentration (ppm)


12:53 12:57 13:02 13:06 13:10 13:14 13:16 13:22 13:27

Concentration (ppm)

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12:08 12:12 12:16 12:20 12:25 12:29 12:33 12:37

Figure1. Levels of (A) halothane and (B) nitrous oxide in the CT

scanner room. A. Average reading 21 ppm (30 min), occupational
exposure limit 10 ppm (8-h time-weighted average). B. Average
reading 787 ppm, occupational exposure limit 100 ppm (8-h timeweighted average).
Reproduced with permission [23].
ppm: Parts permillion.

system and hence gases will be vented into the room. Special
modification or extra scavenging valves should be added to such
systems if possible. One study demonstrated a positive correlation between the environmental and urinary sevoflurane levels
of paediatric anaesthetists and the amount of inhalational
anaesthesia performed in a day using the Jackson-Rees circuit,
despite the concurrent use of an apparently efficient air
exchange system [40].
Anaesthetic exposure of operating theatre staff may be the
highest during head and neck surgery because of their proximity
to the source of gas leakage. However, the airflow of theatre
air-conditioning systems is designed to be optimal in this
region; so, interestingly, auxiliary staff located beyond the main
airflow may be exposed to the highest concentrations of
anaesthetic gases [24].
At room temperature, 1 ml of liquid anaesthetic agent
evaporates to form about 200 ml of vapour. Significant
contamination can occur during the filling of anaesthetic
vaporisers if spillage occurs or if filter caps on vaporisers are
not tightened [36].
Contamination can also arise from the anaesthetic machine
and scavenging systems. This can occur if there are leaks in

the anaesthesia delivery device or in the scavenging systems.

Over-flooding of the scavenging system can result in spillage
of waste gases into the surrounding air. Once waste gases are
scavenged, they are disposed through an active vacuum suction
system or passive recirculation through the operating room
ventilation exhaust. The operating room should have a nonrecirculation ventilation system if passive recirculation is
used. Furthermore, accidental compression or occlusion of the
ventilating hose can result in escape of scavenged gas into
the operating room. Hence, disposal hoses should be regularly
checked and serviced [36].
Other sources of potential contamination include cardiopulmonary bypass machines and cryosurgery. Nitrous oxide
is used in some cryosurgery centres, at rates of up to 90 l/min.
Inhaled anaesthetics are often added to cardiopulmonary
bypass circuits. These gases are usually not scavenged and
significant contamination can occur [36].
American architectural guidelines for medical facilities
require 15 21 air exchanges, of which 3 must be fresh outside
air, to minimise build-up of contaminants [41]. However, if the
non-recirculation type of ventilation is used, fresh outside
air should be used with every air exchange.
5. Effects

of occupationalexposure

The dangers of inhalational anaesthesia to the healthcare

worker were initially recognised to include an increased risk of
spontaneous abortion, cancer, hepatic and renal disease and
congenital abnormalities of offspring [42-44]. However, the
association between waste anaesthetic gases and an increased
incidence of adverse effects was not confirmed. Confounding
variables such as work stresses, radiation and long working
hours were suggested, and studies were mainly retrospective.
Subsequent studies then showed conflicting results[45]. Despite
this, there is evidence of exposure to anaesthetics, especially
nitrous oxide and halogenated gases, being associated with
general health and genotoxic risks[46], and continuing research
reports on the adverse effects of waste anaesthetic gases on
operating roompersonnel.
The principal occupational health hazards associated with
nitrous oxide exposure of healthcare workers include the
potential for effects on the bone marrow caused by the depression of vitamin B12 function, diminished reproductive health and
abusive self-administration [47]. A recent study demonstrated
that exposure to nitrous oxide in theatre nurses is associated with
alterations in vitamin B12 metabolic status compared to those
not exposed. This change was particularly aggravated in subjects
exposed to levels exceeding occupational exposure limit of nitrous
oxide[48]. Although a reduction in Vitamin B12 level was demonstrated, no significant differences were found between both groups
with respect to haematological parameters and folic acid levels.
On the other hand, nitrous oxide has been shown to be teratogenic in experimental animals. At concentrations of 50 75%
delivered to pregnant rats for 24 h during the period of
organogenesis or 0.1% delivered throughout pregnancy, there is

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Occupational exposure to anaesthetic gases: a role for TIVA

Isoflurane ( min)







Isoflurane ( min)

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Figure2. A. Rates measured in the breath of PACU nurses on Friday.

B. Rates measured in the breath of PACU nurses on Monday.
Reproduced with permission [55].
PACU: Post-anesthesia careunit.

an increased frequency of foetal resorptions, visceral and skeletal

abnormalities [49]. Nitrous oxide increases plasma homocysteine
concentrations in a time-dependent manner and hyperhomocysteinaemia may be a risk factor for postoperative cardiovascular morbidity [50]. It has been suggested that nitrous
oxide-induced increases in plasma homocysteine concentration
may be a cause of postoperative cardiovascular morbidity [51].
Chronic exposure to volatile anaesthetics has been associated
with various physiological changes in healthcare staff. In a
Turkish study, anaesthesia and surgery personnel chronically
exposed to inhalation anaesthetics over a period of 3years had
impaired antioxidant defence systems owing to free radical
injury [52]. Plasma and erythrocyte antioxidant activity and trace
element levels were significantly lower (p < 0.05) in 30 operating
room personnel compared with those in 30 controls. This
could lead to an increase in oxygen-derived free radicals that
are highly reactive chemical species involved in ageing and a
variety of clinical disorders [52].
In addition, chronic exposure can inhibit neutrophil
apoptosis and this effect is evident even when isoflurane and
sevoflurane levels are below those recommended [53,54]. It
has been proposed that this could result in an augmented or
prolonged inflammatoryresponse.
Increased occupational exposure to isoflurane has been
associated with depressed central neuro-respiratory activity
among recovery room nurses [55]. This was demonstrated by

measuring the end-expiratory occlusion pressure, which is

the inspiratory pressure generated against complete occlusion
of the airway for a short time, at the onset of inspiration. Exposure to nitrous oxide and isoflurane was found to be significantly
higher on Mondays than on Fridays (Figure 2; p = 0.001).
Breath isoflurane concentrations (mean s.d.) measured on
Mondays increased significantly from 43 30 parts per billion
in pre-shift breath samples to 124 57 parts per billion in
post-shift breath samples (p = 0.002). On Mondays, there
was also a significant decrease in end-expiratory occlusion
pressure from 1.2 0.37 cm H2O in pre-shift samples to
0.85 0.43 cm H2O in post-shift samples (p = 0.05) [55].
An investigation of possible genetic effects showed that
persons administering anaesthesia on a daily basis have a
significantly higher rate of DNA single-strand breaks compared
with controls (p < 0.01) and more breaks were seen in nurse
anaesthetists than in physician anaesthetists [56]. As not every
DNA repair is perfect, such effects could lead to irreversible
DNA damage. A link to an increased risk of developing multiple sclerosis among nurse anaesthetists has been postulated [57].
A study of the literature has even suggested that parental exposure to anaesthetics may increase the level of CNS defects in any
offspring [58]. A correlation has also been shown between the
level of sevoflurane exposure and urinary indices of renal function,
N-acetyl--D-glucosaminidase and glutamine synthetase, in
healthcare workers [59].
These findings are in keeping with those of a review of
occupational exposure to volatile anaesthetics that concluded
their use leads unavoidably to contamination of the ambient
air (Figure 3) and hence to exposure of personnel to these
substances [18]. In operating theatres with modern climate
control and waste anaesthetic gas scavenging systems, occupational exposure is unlikely to exceed threshold limits. However,
occupational exposure from the use of volatile agents in operating theatres with poor air control remains a concern, especially during high-risk procedures such as upper airway surgery,
bronchoscopy and procedures in paediatric patients. This also
holds true for both recovery rooms and ICUs lacking proper
air conditioning and waste gasscavengers.
Despite this evidence, conclusions should be balanced with
the findings from a recent systematic review of the subject,
which was unable to demonstrate an association between
exposure to volatile anaesthetic and health risks [60]. At the
same time, it could not prove that there was no risk involved and
highlighted the importance of minimising exposure to eliminate
possible health risks. Similarly, the ASA Task force on Trace
Anesthetic Gases of the ASA Committee on Occupational
Health of Operating Room Personnel concluded that there are
no current data thus far to suggest that waste anaesthetic gases
are hazardous to women working in a scavenged environment.
Despite this, NIOSH continues to strongly recommend standards for environmental levels of waste anaesthetic gases and
the use of scavenging devices that collect all waste anaesthetic
gases from anaesthetic machines, non-rebreathing systems
and T-tube devices [36].

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Sevoflurrane (ppm)


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5 9 1 3 3 7 7 8 7 3 9 9 4 9 2 4 0 2 0 5 8 8 1 1 8 9 5 0 7 4 6 7 1 0 0 2
:5 :1 :1 :5 :5 :2 :1 :2 :3 :3 :1 :1 :5 :4 :2 :1 :2 :5 :4 :4 :1 :2 :2 :3 :1 :1 :5 :0 :5 :0 :3 :3 :2 :2 :0 :0
59 :24 :49 :13 :38 :03 :28 :54 :18 :43 :08 :33 :57 :22 :47 :24 :47 :10 :28 :53 :18 :43 :08 :33 :58 :23 :47 :13 :37 :03 :26 :51 :16 :41 :06 :31
5 6 6 7 7 8 8 8 9 9 10 10 10 11 11 12 12 13 13 13 14 14 15 15 15 16 16 17 17 18 18 18 19 19 20 20

Figure 3. Example of real-time sevoflurane concentrations in ambient air of the post-anaesthesia care unit over a 14.5-h
working day.
Reproduced with permission [18].

6. Potentialsolutions

Exposure to volatile anaesthetics can be reduced by the use of

appropriate anaesthetic procedures. Gas induction through a
face mask with volatile anaesthetics and the use of open or
semi-open anaesthesia systems are procedures associated with
particularly high exposure. These techniques should be performed only, if at all, in locations with efficient air conditioning
and scavengingdevices.
It has been suggested that if mask anaesthesia with
inhalational anaesthetics is necessary, the laryngeal mask
airway should be used whenever possible [18]. The laryngeal
mask airway, which was first introduced in 1983, represents
a major advance as its snug fit in the hypopharynx provides
a better seal than that of a face mask and should reduce
exposure of personnel to the anaesthetic agent. There have also
been some recent developments in the design of endotracheal
tubes for children that hold some promise [61].
Other possibilities to reduce exposure consist of the use of
double face-masks (with an integrated scavenging system) or
the placement of a local scavenging device close to the
patients head. In addition, low-flow anaesthesia techniques
not only reduce the total amount of volatile anaesthetics
used, but also significantly reduce exposure of personnel to
trace concentrations of these substances. Similarly, nitrous
oxide administered through an on-demand system has been
found to be associated with less atmospheric pollution than a
continuous flow system [62]. The Anaesthetic Conserving
Device (AnaConDa, Sedana Medical, Sundbyberg, Sweden)
is a modified heat-moisture exchanger that has been shown
to be an effective system for maintaining isoflurane levels in

the operating theatre below recommended limits and also for

reducing the volume of anaesthetic required [63].
To reduce exposure within anaesthesia recovery room areas,
an air-conditioning system with an air exchange rate of
500 cubic metres/h per patient without recirculation of
exhausted air seems to be sufficient [64]. In both the recovery
room and the ICU, extra scavenging systems can be mounted
to further reduce exposure of personnel [65], but these units
are generally noisy and, therefore, unpleasant for patients and
personnel. Installation of non-recirculation air conditioning
and scavenging systems can also beexpensive.

Complete avoidance of volatile anaesthetics would circumvent

the problem of contamination of the ambient air and exposure
of healthcare personnel. Intravenous agents are already generally
preferred for induction of anaesthesia and are frequently used
effectively and safely for anaesthesia maintenance. The distinctive feature of total intravenous anaesthesia (TIVA) is the
complete avoidance of both nitrous oxide and volatile anaesthetics. Instead, an air/oxygen mixture is used, an opioid is
given for analgesia and usually propofol is given for induction
and maintenance of anaesthesia. This technique may have a
number of other advantages over inhalation anaesthesia [66].
A comparison of insufflation anaesthesia with halothane
alone versus halothanepropofol in children undergoing direct
laryngobronchoscopy showed that this use of propofol significantly decreased anaesthetic gas exposure in the operating
room. Despite this improvement, both techniques still resulted
in operating room pollution that exceeded the maximum

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Occupational exposure to anaesthetic gases: a role for TIVA

levels of 2 ppm/h recommended by the NIOSH [67]. Similar

results were found in a study comparing sevoflurane with
propofol for induction of anaesthesia followed by sevoflurane
maintenance. Sevoflurane levels in the operating theatre air were
significantly higher when sevoflurane was used for induction
compared with propofol [68].
A comparison of isoflurane with propofol induction
and propofol TIVA on intra-operative neuro-physiological
monitoring during spinal surgery found that isoflurane caused
a dose-dependent decrease in somatosensory evoked potentials,
whereas propofol did not. Isoflurane also decreased trans-cranial
motor evoked potentials in some patients, particularly at a
bispectral index of greater than 55, with no effect observed with
propofol. Based on these results, the authors recommended
propofol for spinal surgery [69].
In general, volatile anaesthetics dilate cerebral blood vessels,
increase cerebral blood volume and can increase intracranial
pressure. They also impair cerebral autoregulation and vascular
reactivity, which are considered undesirable in neuroanaesthesia. Conversely, studies on the effects of propofol have
demonstrated potential avoidance of these undesirable effects
with a reduction in cerebral blood volume and intracranial
pressure, and preservation of cerebral autoregulation and
vascular reactivity [70]. A study comparing intravenous anaesthesia induced and maintained by propofol and fentanyl with
sevoflurane inhalation anaesthesia during endoscopic sinus
surgery found that propofol was associated with significantly
less blood loss than sevoflurane (p < 0.01), thus, making the
procedure technically easier by improving visualisation of the
surgical field [71]. Recovery rates following propofol-based
TIVA are comparable to sevoflurane and desflurane and faster
than isoflurane [72,73].
The introduction of target controlled infusion systems (TCI)
has enabled relatively accurate dosing by continuous infusion.
TCI uses the pooled pharmacokinetic data of a particular drug,
such as propofol, from a large patient population to estimate the
dose required to induce and maintain blood concentrations in
an individual patient. Advantages of TCI include facilitation of
the transition phase from induction to maintenance and the
ability to use the syringe pump in a manner analogous to a calibrated vaporiser, thereby, simplifying TIVA [74]. It is no longer
necessary to use bolus intravenous agents for induction and then
convert to inhalational agents for maintenance ofanaesthesia.
Several clinical trials have compared TIVA techniques with
those of volatile induction and maintenance anaesthesia. In a
study of 40 patients undergoing spinal surgery, TIVA with
propofol using target control infusion was found to be
equally acceptable to patients as volatile induction and maintenance anaesthesia with sevoflurane [74]. Induction with
propofol was faster than with sevoflurane, but also associated
with more involuntary movements. The number of interventions
by the anaesthesiologist was doubled with sevoflurane compared with propofol but emergence times, haemodynamics,
and postoperative nausea, vomiting and pain were similar
with the two techniques [74].

A randomised, prospective study comparing sevoflurane- and

propofol-based anaesthesia in 186patients undergoing elective
surgical procedures of 1 3h showed that the overall frequency
of complication-free induction, maintenance and emergence
did not differ between the two anaesthetic groups [75].
However, side effects involving airway excitement were more
prevalent during mask induction with sevoflurane as compared
with propofol[75]. In addition, the time required for an inhaled
induction and intubation was longer with sevoflurane anaesthesia compared with intravenous induction with propofol. It
is worth noting that nitrous oxide was a component of the
anaesthetic technique in both groups in this study, and so it
was not true TIVA, and may have been responsible for the
incidence of vomiting in patients treated with propofol.
Remifentanil is a potent opioid with a very short contextsensitive half-life, irrespective of the duration of infusion.
This opioid is a viable alternative to nitrous oxide [76] and
may have other particular advantages [77]. There is now
strong evidence that volatile anaesthetics are emetogenic and
that there are no meaningful differences among halothane,
enflurane, isoflurane, sevoflurane and desflurane in this
respect [78]. A recent, large trial reported that the use of
propofol, instead of volatile agents, reduced the risk of postoperative nausea and vomiting by 19% and use of nitrogen,
in place of nitrous oxide, reduced the risk by 12% [79].
An assessment of postoperative patient well-being after
propofol-based TIVA or propofol-based induction followed
by sevoflurane maintenance anaesthesia showed that Adjective
Mood Scale and StateTraitAnxiety Inventory scores were
significantly better 90 min after TIVA versus the comparator
regimen (p = 0.02 and 0.05, respectively) [80]. The incidence of
postoperative nausea was also significantly reduced after TIVA
compared with inhalation anaesthesia at 90 min (p < 0.001)
and 24 h (p = 0.001). Postoperative pain was comparable
between groups at these time points. It was proposed that
study designs with a pragmatic approach of daily clinical
practice and the shortcomings of surrogate end points may be
responsible for other studies failing to show such a difference in
patient well-being [80]. By applying a strict anaesthetic regimen
with minimal variations, a significant difference in psychometric
testing was revealed. New research suggests that inhalation
anaesthetics are linked more closely with the formation of
Alzheimers-related plaques in the brain than those given
intravenously [81]. Tanzi and co-workers have also shown that
at clinically relevant concentrations, isoflurane induces apoptosis, alters amyloid precursor protein processing and increases
A peptide generation in a human neuroglioma cell line [82].
Propofol has antioxidant activities compared with conventional volatile anaesthetics [83]. This potent antioxidant activity
protects erythrocytes and other cells against surgical-induced
oxidative stress and ischaemia reperfusion injury [84,85]. As a
result, it reduced postoperative anaemia in a comparison
with sevoflurane [86]. On the other hand, propofol induces
neutrophil apoptosis by the mechanism of caspase activation
and cytochrome C release from mitochondria [87].

Expert Opin. Drug Saf. (2009) 8(4)

Irwin, Trinh & Yao

8. Conclusion

Expert Opin. Drug Saf. Downloaded from by UB Kiel on 10/28/14

For personal use only.

The effects of occupational exposure to volatile anaesthetic

agents such as isoflurane are well recognised [88] but those
associated with newer agents are less well defined. Effects
on antioxidant activity of plasma and erythrocytes and
inhibition of neutrophil apoptosis have been shown. Other
effects include depression of central neuro-respiratory activity,
DNA breaks, effects on cerebral blood circulation, brain
amyloid build-up and altered renal function. Although
some studies report anaesthetic levels in operating theatres
to be in national guideline levels, many report higher levels,
particularly in areas lacking proper air conditioning and
waste gas scavengers.
9. Expert


It is difficult to determine what levels are actuallysafe.

Possible solutions to reduce occupational exposure to
inhalational anaesthetics include altering anaesthetic procedures,




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such as use of low-flow systems, use of on-demand rather

than continuous flow systems and double face-masks. Non
re-circulating air-conditioning and air scavenging systems
further reduce exposure of healthcare personnel. Complete
avoidance of volatile anaesthetics with TIVA would
eliminate the problem of anaesthetic environmental pollution and occupational exposure through contamination of
the ambient air. Intravenous agents are often preferred for
anaesthesia induction. The advent of reliable TCI systems
has made intravenous anaesthesia relatively simple and TCI
has now been extended to include paediatric anaesthesia and
remifentanil administration.

Declaration ofinterest
The authors thank D Burton and H Wills from Caudex
Medical, who provided some background material and
arranged permission to reproduce figures. Caudex Medical
was funded by AstraZeneca. The authors have received no
payment in preparation of this manuscript.

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Michael G Irwin1, Theresa Trinh2 & Che-Lin Yao3,4
for correspondence
1Professor and Head,
The University of Hong Kong,
Queen Mary Hospital,
Department of Anaesthesiology,
Room 424, Block K, Hong Kong
Tel: +852 28553303; Fax: +852 28551654;
2Clinical Associate,
The University of Hong Kong,
Queen Mary Hospital,
Department of Anaesthesiology,
Room 424, Block K, Hong Kong
3Associate Consultant,
Singapore General Hospital,
Department of Anaesthesia & Surgical Intensive Care,
Outram Road,
Singapore 169608, Singapore
4Honorary Clinical Associate,
The University of Hong Kong,
Queen Mary Hospital,
Department of Anaesthesiology,
Room 424, Block K,
Hong Kong