PHARMACOLOGY

Inhalational anaesthesia Learning objectives

Elliott Bertram-Ralph After reading this article, you should be able to:
Muataz Amare C describe the properties of the ideal inhalational agent
C discuss the factors that influence the onset of action and potency

of inhalational agents, their theoretical mechanism of action, and

Abstract the impact of their molecular structure
C understand the general and specific effects of commonly used
The use of inhalational agents for the induction and maintenance of
anaesthesia in clinical practice has undergone significant advances inhalational agents on organ systems
C explain how inhalational anaesthesia is delivered and monitored
in safety and effectiveness since its introduction in the 1800s. In the
United Kingdom, desflurane, sevoflurane and isoflurane are the most in clinical practice
C describe the effects that inhalational anaesthesia has on the
commonly used agents. The ideal inhalational anaesthetic would
have a low blood:gas solubility coefficient and a high oil:gas coeffi- environment
cient, which would generate a fast onset and high potency, respec-
tively. Inhaled agents are delivered by vaporizers that are specific to
effects, the equipment used, appropriate monitoring and any
each agent, and concentrations are closely measured to deliver safe
considerations that should be made prior to use.
anaesthesia. Expired concentrations of the volatile are used to monitor
alveolar concentrations, which are used as a surrogate for the partial
Ideal inhalational agent
pressure in the brain, governing the effect of the agent. Unfortunately,
inhaled anaesthesia is a cause of global warming, with inhalational The ideal properties of an inhalational agent can be considered in
agents representing 5% of the carbon footprint of the whole NHS. terms of their physical, pharmacokinetic and pharmacodynamic
Consequently, their use needs to be tightly regulated. properties, with examples listed in Table 1. There is no current
Keywords Anaesthesia; gases; global warming; inhalational; MAC; agent in clinical practice which has all the desired characteristics
partial pressure; potency; solubility; SVP; vaporizer listed.
The introduction of intravenous anaesthetic agents and potent
Royal College of Anaesthetists CPD Matrix: 1A01, 1A02, 1A03, 2A04 opioids has allowed lower concentrations of inhaled agents to be
used, therefore the safety margin of inhaled agents is less of an
issue.

Introduction What affects an inhalational agent’s onset and potency?

Early attempts at anaesthesia involved crude techniques to Table 1 describes how an inhalational agent with a low blood:gas
render patients unconscious for painful procedures. For example, and a high oil:gas partition coefficient is desirable, and these are
ethanol, herbal mixtures and even head trauma or bilateral oc- the characteristics which affect how quickly it works and the
clusion of the carotid arteries were used; however, these concentration needed to produce anaesthesia. The coefficients of
methods were both ineffective and dangerous. Inhalational the different agents are listed in Table 2.
anaesthesia was first implemented in the 1800s with the intro- The lower the blood:gas solubility, the faster the onset. The
duction of agents including ether, chloroform and nitrous oxide. blood:gas coefficient is ‘the ratio of anaesthetic in the blood to
However, there were many safety issues, limited knowledge and that in gas when the two phases are of equal volume and in
no guidelines for safe use in clinical practice. As a result, further equilibrium at 37
C.’ For example, a blood:gas partition coeffi-
research was undertaken to further understanding and support cient of 0.69 for sevoflurane means that at equilibrium, a volume
the development of alternative agents. of blood will contain 0.69 the volume of sevoflurane compared
Modern inhalational agents include the fluorinated ethers with an equal volume of alveolar gas when the partial pressures
isoflurane, sevoflurane and desflurane, which have proven to be are the same at 37
C. It is the main determinant of uptake of an
safer and more reliable during complex modern surgical pro- agent by pulmonary blood and therefore the rate of emergence
cedures. These drugs are used in the operating theatre for both and induction using an inhaled anaesthetic agent. The effect of
induction and maintenance of anaesthesia, but their exact the anaesthetic agent is related to the partial pressure it exerts in
mechanism of action remains unknown. the blood and therefore the brain, and not to the absolute
This article aims to review inhalational anaesthesia, the po- quantities dissolved.
tential mechanisms of action of the various agents, their side When an anaesthetic agent is poorly soluble, it will enter the
liquid phase slowly and exert a higher partial pressure in the
blood and brain, therefore having a faster onset of action. The
fractional alveolar concentration of inhaled agent (FA) increases
Elliott Bertram-Ralph MBChB BSc FRCA is a ST5 ICM/Anaesthesia quickly towards equilibration with the fractional inspired con-
trainee at Salford Royal Hospital, Manchester, UK. Conflicts of centration of the agent leaving the anaesthetic circuit (Fi). This
interest: none declared. means a higher FA/Fi ratio is obtained more quickly.
Muataz Amare MB BCh FRCA is a Consultant Anaesthetist at Salford Highly soluble agents have low partial pressures in the blood
Royal Hospital, Manchester, UK. Conflicts of interest: none declared. and more molecules are needed to saturate the liquid phase

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 PHARMACOLOGY

Properties of an ideal inhalational anaesthetic agent1

Physical Pharmacokinetic Pharmacodynamics

C Low cost C Low blood:gas partition coefficient Central nervous system (CNS)
C Easy to manufacture C High oil:gas partition coefficient C Only effect the CNS causing anaesthesia
C Environmentally friendly C Excreted rapidly and unchanged from the C Not epileptogenic
C Stable and non-flammable lungs C No change in cerebral blood flow (CBF) or
C Liquid at room temperature (boiling point intracranial pressure (ICP)
above ambient temperature) C Rapid reversible
C Long shelf life C Smooth induction
C Non irritant C Analgesic properties
C Low specific heat capacity Cardiovascular (CV)
C Low latent heat of vaporization C No depression
C High saturated vapor pressure C Stable heart rate
C Preservative free C No effect on coronary blood flow
Respiratory
C Bronchodilation
C No respiratory depression, breath holding,
laryngospasm, or increase in secretions
Other
C No effect on kidneys or liver
C Muscle relaxation
C Will not cause malignant hyperthermia
C No interactions
C Safe in pregnancy
C Anti-emetic
C No interactions with other anaesthetic
agents and allows use of high FiO2

Table 1

before the partial pressure increases. The molecules readily enter
If the MV is increased, it leads to more anaesthetic agent
the bloodstream from the alveoli, therefore alveolar concentra- being delivered to the alveolus, a higher alveolar con-
tion and partial pressure remain low. As a result, the brain partial centration, and a faster onset.
pressure rises slowly, and anaesthetic onset takes longer. This  Functional residual capacity (FRC)
means a higher FA/Fi ratio is obtained more slowly.
A large FRC will dilute the anaesthetic agent, which will
There are other factors which influence the speed of onset of mean that the alveolar concentration will rise more
an agent. They all relate to the balance between uptake of slowly and slow the onset of anaesthesia.
anaesthetic into the blood from the alveoli and delivery of drug to  Cardiac output (CO)
the alveoli.
If the CO is high, it leads to greater pulmonary blood
 Minute ventilation (MV) flow (if there is no shunt, cardiac output ¼ pulmonary

Physiochemical properties of inhaled anaesthetic agents1

Agent MW BP (
C) SVP MAC Blood:gas Oil:gas Odour % Metabolized and metabolites
at 20
C coefficient coefficient
at 37
C at 37
C

Desflurane 168 23.5 89.2 6.6 0.45 29 Pungent 0.02, trifluoroacetic acid
N20 44 -88 5200 105 0.47 1.4 Odourless 0.01, nitrogen
Sevoflurane 200.1 58.5 22.7 1.8e2.2 0.7 80 Non-irritant 3.5, inorganic and organic fluorides,
and compound AeE
Isoflurane 184.5 48.5 33.2 1.17 1.4 98 Irritant 0.2, trifluoroacetic acid and F
Enflurane 184.5 56.5 23.3 1.68 1.8 98 Non-irritant 2, Inorganic and organic fluorides
Halothane 197 50.2 32.3 0.75 2.4 224 Non-irritant 20, trifluoroacetic acid, Cl and Br
Xenon 131 108 e 71 0.14 1.9 Odourless Nil

Table 2

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 PHARMACOLOGY

blood flow). This means that the anaesthetic agent is

taken up more quickly from the alveolus and the partial
pressure rises slowly. Therefore, paradoxically, a higher
CO causes a slower onset of anaesthesia.

However, cerebral perfusion is still important. In a low
CO state, if cerebral perfusion is reduced, onset of
anaesthesia will be slow.
 Inspired concentration

The concentration of anaesthetic delivered to the alve-
olus depends on several factors. This includes the con-
centration of anaesthetic agent delivered, the fresh gas
flow and volume of the breathing circuit. The higher the
concentration delivered, the faster the onset.
 Shunt

Shunts produce a delay in the rise of the partial pressure
of the anaesthetic agent within the blood. Insoluble
gases are less able to compensate for the unventilated
alveoli compared with soluble gases.
 Concentration effect and second gas effect using nitrous
oxide (N2O)

The concentration effect occurs with N2O causing a Figure 1
disproportionate rise in the concentration of the other the mean alveolar concentration (MAC) would be constant for all
inspired gases in the alveoli. N2O is twenty times more agents, this is not the case. For example, enflurane and isoflurane
soluble than oxygen (O2) and nitrogen (N2). During in- are structural isomers with the same oil:gas coefficient of 98, but
duction, the N2O entering the pulmonary capillaries is there is a large difference between their MAC values (isoflurane
greater than N2 leaving the blood into the alveolus. This is 1.17 and enflurane is 1.68).1 MAC values and how they affect
means the volume within the alveolus decreases, which inhalational anaesthetics is described below.
increases the fractional concentration of the remaining
gases. Ventilation is also augmented as tracheal gas is How do inhalational agents exert their effects?
drawn into the alveolus due to this reduced alveolar
volume. The precise mechanism of action of anaesthetic agents is un-

The second gas effect occurs when N2O is being used known, but several hypotheses have been proposed. The Meyer-
with an inhalational agent and this reduced volume Overton hypothesis was put forward in 1899, suggesting that
within the alveolus as described above increases the greater anaesthetic potency was associated with greater lipid
concentration of the inhalational agent, resulting in a solubility of the agent. It was also noted that the agents were
quicker onset time. additive when used simultaneously. The critical volume hy-
The relationship between inspired concentration and alveolar potheses by Miller and Smith (1973) expanded on this further,
concentration can be represented graphically as shown in
Figure 1. Different agents take different times to reach steady
state, meaning an equilibrium between the concentration of agent
in the blood and the concentration in the alveolus. The time it
takes to reach steady state is determined by their blood:gas co-
efficient. As described, agents with a lower blood:gas coefficients
take less time to reach steady state. FA/Fi is the fractional alveolar
concentration of inhaled agent versus the fractional inspired
concentration of inhaled agent leaving the anaesthetic circuit,
when this equals 1, the agent is at steady state.
The oil:gas partition coefficient measures an agent’s lipid sol-
ubility, and this determines its potency. The potency of a drug is a
measure of the drug activity and how much of the drug is needed to
produce an effect of a given intensity. The definition of an oil:gas
partition coefficient is ‘the ratio of gas in adipose tissue compared
with alveolar gas at equilibrium, which occurs when partial pres-
sures and volumes are equal between the 2 phases at 37
C.’ See
Table 2 for inhalational agent’s oil:gas partition coefficient values.
The Meyer-Overton hypothesis shows that there is a direct
relationship between the oil:gas coefficient of anaesthetic gases
and their potency. This is shown in Figure 2. However, if this
theory were to be true, the product of the oil:gas coefficient and Figure 2

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 PHARMACOLOGY

suggesting that synaptic transmission is impaired when enough

hydrophobic anaesthetic agent is dissolved in the cell membrane,
causing expansion and disruption of ion channels.1
However, the above theories are flawed. Notably, stereoiso-
mers (eg isoflurane and enflurane) have significantly different
potency despite a very similar oil:gas coefficient, and additionally
not all highly soluble drugs exert an anaesthetic effect.
More recently, protein targets have been suggested to be
responsible for the anaesthetic effects of inhaled agents. Binding
sites for the anaesthetic drugs have been found on cell membrane
proteins, with many ion channels and proteins proposed to be
involved. Inhalational agents can affect pre-synaptic release of
neurotransmitters and post-synaptic response threshold. For
example, potentiation at the GABAA and glycine receptors post-
synaptically and inhibition of the excitatory presynaptic NMDA
and nicotinic receptors are thought to have key roles in reducing
transmission.
Two-pore domain potassium channels have more recently
been shown to be influenced by anaesthetic inhalational agents.
These channels have a leaking current which influences the
baseline resting membrane potential of cells and influences the
likelihood of neuronal action potentials. Many volatile anaes-
thetic agents have been shown to augment the effect of these
channels, leading to hyperpolarization, and causing anaesthesia.
The effects of altering these proteins lead to general anaes-
thesia. Macroscopically, at the spinal level, inhalational anaes-
thetics block noxious afferent pain information reaching the
cerebral cortex via the thalamus, and they also reduce reflex
movements in response to pain by blocking spinal efferent ac-
tivity. Supraspinally, cerebral blood flow and metabolism are
reduced as shown by EEG and tomographic assessment, causing
amnesia and hypnosis.2

Structure of inhaled anaesthetic agents

Most volatiles in current clinical use are halogenated ethers
(except halothane, xenon, and nitrous oxide). Their structures Figure 3
are shown in Figure 3. An ether is an organic molecule con-
taining an ether group within its structure (an oxygen atom
to the potency of an inhalational anaesthetic agent; this means an
bonded to two alkyl groups). The halogenated ethers have a
anaesthetic agent with a high MAC has a low potency and lower
halogen atom such as fluorine, chlorine, bromine and iodine,
oil:gas partition coefficient. See Table 2 for the MAC values of the
substituted for a hydrogen atom. Halogens are members of
various inhaled anaesthetic agents.
group VII of the periodic table. Fluorine is the lightest and most
MAC is the ED50 (effective dose in 50% of subjects), and as a
electronegative of the halogens and reduces the molecular
result 50% of subjects may have a higher or lower MAC. MAC
weight and stabilizes ethers. It increases the saturated vapour
is spread as a normal distribution across patients, but variation
pressure of liquids and therefore they evaporate less easily.
is generally small. MAC is an indirect measure of the
Halogenation reduces flammability which was a particular
anaesthetic effect on the brain and is used because there is no
problem with the early inhaled anaesthetic agent diethyl ether
direct measurement available. The expired concentration of
(non-halogenated ether). Not all halogenated ethers have
the anaesthetic agent is measured using a vapour analyser
anaesthetic effects.3
(commonly, infrared spectrometers) on the anaesthetic ma-
chine and is felt to be a surrogate for alveolar concentration. It
Minimum alveolar concentration (MAC)
is known there is a diffusion gradient between the alveolus, to
MAC is defined as the minimum alveolar concentration of an the arterial blood, to the brain, but when the agent reaches
inhalational anaesthetic agent, at sea level (1 atmosphere) and steady state, the alveolar concentration is the same as the
with an FiO2 of 100%, that prevents movement in response to a concentration in the brain. When using several anaesthetic
standard surgical stimulus in 50% of patients. A standard sur- inhaled agents, the MAC is additive. For example, a MAC of 0.5
gical stimulus is defined as a 1cm deep  1cm wide skin incision for sevoflurane and desflurane will add together to give a total
on the ventral aspect of the lower arm. MAC is inversely related MAC of 1.0.

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 PHARMACOLOGY

Other terms are used to describe the MAC: Adverse effects

 MACawake is the MAC of an inhalational agent at which
See Table 3 for a list of the potential adverse effects on organ
50% of subjects no longer respond appropriately to com-
systems of the commonly used agents. There are several specific
mands. It is largely used on emergence when the patient
side effects that are worth further discussion (see Table 4).
can open eyes and follow commands. It is worth noting
airway reflexes return at a more awake state. Compound AeE
 MACBAR is the MAC where 50% of patients will have a When using soda lime and baralyme carbon dioxide absorbers
blunted autonomic nervous system response (increase in with the volatile sevoflurane, a reaction occurs which produces
heart rate or blood pressure) to the standard surgical several substances. These include compound A, B, C, D and E
stimulus. which are formed when sevoflurane is dehydrohalogenated in
The MAC is a dynamic figure that can be altered by various the presence of potassium hydroxide in the absorber. Compound
factors.4 A is a fluoro methyl ether and has been shown to be toxic, as it is
degraded into a nephrotoxic substance. In rat models, the renal
What affects the rate of recovery from anaesthesia from
damage is dose dependent, however in humans, the plasma
inhalational agents?
levels are never high enough clinically to induce any effect.
The speed of recovery of anaesthesia from an inhaled agent is Factors which increase the production of compound A include
dependent on several factors. The aim is to reduce the partial high concentrations of sevoflurane, higher temperatures, low
pressure of the agent within the brain to allow emergence. fresh gas flow and using baralyme.
Firstly, exhalation of the anaesthetic agent from the lung un-
changed is the most important method of removal of anaesthetic Carbon monoxide
from the body to allow recovery. On induction, anaesthesia relies Carbon monoxide (CO) is produced when inhalational agents
on the gradient of inhalational anaesthetic established from the with the CHF2 moiety, such as desflurane, isoflurane and
alveolus to the brain. On recovery, this gradient is reversed so enflurane, are used on dried out and warm (desiccated) soda
that the brain has a higher concentration than the alveolus. The lime. Soda lime becomes dried out when it has been left unused
rate of recovery is dependent on the size of this gradient, a larger for a long period of time. This CO formation can become clini-
gradient corresponds with a quicker recovery. Therefore, a high cally significant in smokers. Higher temperatures, higher anaes-
MV, a high fresh gas flow, and no volatile being administered via thetic concentration, desflurane use, very dry absorbent and
the vaporizer contribute to a quicker recovery. baralyme all increase the production of CO.
Prolonged use of inhaled anaesthetic causes saturation of
Coronary steel
tissues with a less plentiful blood flow alongside the well-
Isoflurane is a coronary vasodilator and affects arterioles most
perfused vessel rich organs such as the brain, heart, liver, and
acutely. By dilating the vessels, it diverts blood away from the
kidneys. The vessel-rich tissues are both the first to saturate with
poorly perfused stenotic regions of the myocardial circulation,
and remove the anaesthetic agents due to their high perfusion
which are therefore not able to dilate, inducing ischaemia. As a
(both processes taking around 5e10 minutes). These processes
result of this and the tachycardia it can induce, isoflurane was
in muscle, skin and fat take longer due to a lower perfusion,
avoided in patients with known coronary artery disease. How-
which can delay emergence significantly. Filling of the poorly
ever, volatile agents rarely cause this phenomenon due to them
perfused compartments also occurs more quickly when using
often reducing myocardial oxygen demand.
agents that have a high lipid solubility, which can also slow the
recovery rate. Tec 6 vaporizers
Metabolism of the anaesthetic agent via the cytochrome P Desflurane has a boiling point of 23.5
C and a very high satu-
(CYP) 450 system is also involved in removal of the drug from rated vapour pressure of 88kPa. This means it is very volatile and
the brain and recovery. All volatile agents are metabolized to it would be dangerous to administer with a standard vaporizer.
varying degrees by these enzymes, mainly in the liver but also in Small changes in room temperature would lead to large changes
the kidneys. Metabolism occurs through oxidation and removal in saturated vapour pressure changing the depth of anaesthesia.
of the halogens from the drug. This process can produce toxic It is therefore administered using a Tec 6 electronic vaporizer
metabolites, for example trifluoroacetic acid on breakdown of which is heated to 39
C and kept at 2 atmospheres of pressure.
desflurane, halothane and isoflurane, and inorganic fluorides By heating desflurane to 39, the saturated vapour pressure is
with enflurane and sevoflurane breakdown. These metabolites increased to 200 kPa, and a pressure reducing valve is used to
are nephrotoxic and hepatotoxic. More lipid-soluble agents are introduce the gas into the fresh gas flow. By keeping the tem-
metabolized more quickly than less soluble agents. The chemical perature stable and known, the quantity of anaesthetic being
structure of the agent also affects its metabolism, with CeBr delivered is can be more accurately determined.
being the least stable Cehalogen bond, followed by the CeCl
and CeF halogen bonds. Table two shows how extensively Halothane hepatitis
each agent is metabolized, and the metabolites produced. Halothane is the most extensively metabolized inhalational
There is also a small amount of volatile anaesthetic which is agent. There are two types of hepatitis associated with halothane
lost through the skin, but the amount is insignificant. All these use and its metabolism. Type one is mild and self-limiting. It
processes are responsible for the speed of recovery from occurs 25e30% of the time using halothane and leads to mild
anaesthesia. increases in liver enzymes and alters drug metabolism after use.

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 PHARMACOLOGY

Factors effecting mean alveolar concentration4

Decreasing MAC Increasing MAC

Patient age higher (w10% for every 10 years) Decreasing age (peaks at 6 months and slowly declines as child ages)
Neonatal period Hyperthermia
Pregnant patient Chronic alcohol and opioid use
Hypothermia Anxiety and Sympathetic stimulation
Hypovolaemia
Hypoxia and Hypocapnia
Anaemia
Acute alcohol intoxication

Table 3

It is thought to be due to hepatic hypoxia caused by halothane  Gases composed of two dissimilar molecules (e.g. carbon
metabolism in the liver leading to this derangement. dioxide and nitrous oxide) absorb infrared radiation of a
Type two halothane hepatitis is less common but leads to particular wavelength and convert the energy into molec-
necrosis of hepatocytes and fulminant liver failure. The incidence ular vibration.
is low, with a reported range between 1 adult patient in every  Absorption of a wavelength of infrared radiation by a
3500e35,000 cases; however, there is a very high mortality rate volatile agent is proportional to the concentration of the
(50e70%). It is caused by an autoimmune response. An inter- gas and allows its concentration to be measured.
mediate metabolite called trifluoroacetyl chloride (TFA) cova- Using these principles, an infrared gas analyser uses an
lently binds to hepatocytes and forms a complex that induces infrared light source that passes a light beam through a filter to
antibody formation. Risk factors include repeated exposure, obtain radiation of a specific wavelength, which is passed
obesity, female gender and hypoxia. It is recommended to avoid through the sample chamber. The required wavelength of radi-
halothane use if there has been a previous reaction to the drug, if ation is dependent on the gas being measured. A proportion of
the patient has had the drug within the previous 3 months or if the light sample is absorbed by the gas during measurement.
they have a history of unexplained liver injury or jaundice. Once the light has left the sample chamber a detector then
measures the intensity of the light signal remaining, and the re-
Seizure activity sults are then displayed for interpretation. Often, reference
Enflurane is associated with abnormal epileptiform activity on chambers that do not contain the gas being measured are used
EEG, especially if it is associated with hypocapnia. for calibration to improve accuracy. Water vapour can also in-
fluence the result, so gases are dried before they are analysed.
Dysrhythmias
Other molecules can interfere with the measurement of vol-
Halothane is the most arrhythmogenic inhalational agent. It
atile agents at their specific wavelengths. Collision broadening
sensitizes the myocardium to circulating catecholamines, which
occurs when carbon dioxide and nitrous oxide interact with one
can induce malignant arrythmias. This is worsened with an
another. Normally the absorption peaks of infrared light for
acidosis and hypercapnia. It has also been known to induce
carbon dioxide and nitrous oxide are between 4 and 5 mm.
bradycardias, junctional rhythms, and ventricular ectopic beats.
However, the energy absorbed by one molecule of carbon diox-
Nephrotoxicity ide when it has already absorbed light energy is transferred to a
When inhaled anaesthetic agents undergo metabolism via the molecule of nitrous oxide when they collide. This means that the
CYP450 system they release halogen ions which are potentially carbon dioxide molecule can absorb more energy giving a
nephrotoxic, although this does not appear to be clinically sig- broader absorption spectrum of between 3 and 12 mm. This will
nificant with sevoflurane which undergoes significant interfere with and broaden the absorption peaks of volatile
defluorination. agents which absorb infrared between 8 and 13 mm. However,
modern systems compensate for this phenomenon.5
Measuring concentrations of volatile agents Other less common means of measuring vapours include mass
spectroscopy, gas chromatography, the piezoelectric effect using
A vapour analyser is essential whenever volatile anaesthesia is quartz crystals, raman spectroscopy, photoacoustic spectros-
used for anaesthesia. The concentration of volatile anaesthetics copy, refractometers and katharometers.
can be measured by several means. In theatre, most systems use
infrared spectroscopy.
Vaporizers
Infrared absorption spectroscopy relies on several principles:
 Beer’s law states that absorption of radiation increases as Some inhalational agents are volatile liquids (for example, des-
the concentration of a substance increases. flurane, sevoflurane, enflurane) which need to be vaporized to
 Lambert’s law states that the intensity of transmitted light be delivered via inhalation to produce general anaesthesia. A gas
reduces exponentially as the distance travelled through the is defined as a substance in its gaseous state in a temperature
substance increases. above its critical temperature. A vapour is a substance which is

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 ANAESTHESIA AND INTENSIVE CARE MEDICINE 23:1

Commonly used inhalational agents and their effects on organ systems1

Sevoflurane Isoflurane Desflurane

Structure and molecular weight C4H3F7O C3H2F5O C3H2F6O

200 184.5 168
Vapour pressure at 20
C 21.3kPa 32kPa 88.5kPa
Boiling point 58.6
C 48.5
C 22.8
C
CV Vasodilation, SVR Y- dose Vasodilation, SVR YYe Vasodilation, SVR YYe
dependent dose dependent dose dependent
Myocardial depressant, HR [ over 1.0 MAC Myocardial depressant,
contractility Y and CO Y and Myocardial depressant, contractility Y and CO Y and
MAP Y contractility Y and CO MAP YY
Can [ QT interval maintained (due to HR) and HR [
HR no change MAP YY (due to SVR) Can [ QT interval
Can [ QT interval
Coronary steal and dilates
coronary arteries
Respiratory Y MV Y VT and [ RR Y MV YVT and [ RR Y MV YVT and [ RR

PHARMACOLOGY
[PaCO2 [PaCO2 [PaCO2
YY ventilatory response to YBronchial tone YBronchial tone
66

PaO2 Irritant to airway Irritant to airway

Y Sensitivity to PaCO2 Secretions [ Secretions [
Irritant to airway YY ventilatory response to YY ventilatory response to
Reduces bronchial tone PaO2 PaO2
Non irritant to airway YY Sensitivity to PaCO2 Y Sensitivity to PaCO2
Irritant to airway Irritant to airway
Secretions [ Secretions [
CNS Vasodilation [CBF and [ICP Vasodilation [ CBF and [ Vasodilation [[ CBF and
at over 1.5 MAC [ICP over 1.0 MAC [ [ ICP over 0.5 MAC
YYYCMRO2 YYYCMRO2 YYYCMRO2
Uncouples relationship Uncouples relationship Uncouples relationship
between PaCO2 and CBF between PaCO2 and CBF between PaCO2 and CBF
Other Dose dependent Y in uterine Dose dependent Y in uterine Dose dependent Y in uterine
tone, Y renal blood flow tone, Y renal blood flow tone, Y renal blood flow
Can trigger MH Can trigger MH Can trigger MH
Ó 2021 Published by Elsevier Ltd.

Compound A e E Skeletal muscle relaxation Skeletal muscle relaxation

Ischaemic preconditioning Ischaemic preconditioning Ischaemic preconditioning
Skeletal muscle relaxation CO poisoning possible Vaporizer requirements- Tec
PONV PONV 6e39
C and 2 ATM
CO poisoning possible
PONV

Table 4
 PHARMACOLOGY

in the gas phase at a temperature below its critical temperature. aneroid bellows which contract with a reduction in temperature
Nitrous oxide and xenon are gases at ambient temperature and to obstruct the bypass channel. The vaporizer is also constructed
do not need vaporization prior to delivery. of materials of high specific heat capacity and thermal conduc-
When delivering vapours, a vaporizer is needed to prevent tivity which act as a heat sink.6
delivery of excessively high concentrations of anaesthetic at The way atmospheric pressure affects vaporizer use can be
room temperature and pressure. The saturated vapour pressure considered when using them at altitude. At varying altitudes, the
(SVP) of a volatile anaesthetic is the partial pressure exerted by SVP does not change, so the partial pressure leaving the chamber
the vapour when in equilibrium with the liquid phase (equal is the same. However, the atmospheric pressure does drop at
number of particles leaving and entering each phase). The SVP higher altitudes, and rises at lower altitudes. Consequently, the
determines the concentration of vapour above the liquid anaes- SVP becomes a greater proportion of the atmospheric pressure.
thetic agent. Without a vaporizer, at room temperature and So, if a vaporizer is set at 1%, at a higher altitude with an at-
pressure, desflurane (SVP of 88.2kPa at 20
C) can achieve a mospheric pressure of 50.5kPa (compared with sea level atmo-
maximum concentration of 87% and sevoflurane (SVP of spheric pressure of 101kPa), it will deliver 2%. However, 1% of
22.7kPa at 20
C) achieves a concentration of 22.4%. Both these 101kPa is the same as 2% of 50.5kPa, therefore it will deliver the
concentrations are far too high for safe anaesthesia and need to same partial pressure and as a result the settings would not need
be controlled with a vaporizer. Therefore, a higher SVP means a to be changed.
lower gas flow is needed through the vaporizer to achieve an
appropriate concentration for anaesthesia. Nitrous oxide
A plenum vaporizer is the most commonly used device on
anaesthetic machines in theatre. It receives gas flow which it Nitrous oxide is largely used to supplement general anaesthetic
splits into two streams with variable flows. One stream is and is commonly used as a potent analgesic in labour using
directed through a chamber with the vapour in and is fully Entonox (50:50 mixture of oxygen and nitrous oxide). It is a
saturated with the agent, and the other larger stream is directed colourless gas that is non-flammable. It is stored often as size E
through a bypass chamber. The proportions of flow through each cylinders on anaesthetic machines (1800 L) or size J cylinders on
chamber are determined by the dial on the vaporizer. The two manifolds (18,000 L).
unidirectional streams then join, and an accurate concentration It is produced by heating ammonium nitrate to 170e240
C;
of anaesthetic is formed to be delivered to the patient. To ensure however, contaminants are produced when the thermal decom-
a precise concentration of anaesthetic is supplied, the vaporizing position is not performed accurately. These contaminants include
chamber needs to saturate the gas fully, even at higher gas flows. ammonia, nitrogen dioxide and nitric oxide which can cause
This is achieved with metal or Teflon wicks which act via airway irritation and fibrosis after longer periods of exposure.
capillary action to generate a large surface area for the gas to These toxic gases are removed by the manufacturers.
ensure full saturation, and baffles which direct the gas onto the It is stored in cylinders at a gauge pressure of 4400 kPa in
surface of the liquid. French blue cylinders as a liquid with its vapour phase above. As
Vaporizers are specific to each agents SVP to enable an ac- a result, the way the cylinders are filled need to be carefully
curate concentration to be delivered. Varying SVPs of agents at a managed. The filling ratio is the weight of the fluid in the cylinder
given temperature mean that different concentrations would be divided by the weight of fluid which would fill the cylinder. In
delivered for a given dialled percentage if volatiles were swapped the UK, this ratio should equal 0.75. Liquid is less compressible
between vaporizers. Desflurane has an SVP at 20
C of 88kPa and than gas, so to prevent large rises in pressure with temperature
a boiling point of 23.5
C. This means it needs a particular rises, the cylinders should not be filled entirely with liquid.
vaporizer to avoid the high concentrations that passive vapor- The pressure in the cylinder does not indicate how well filled
ization would cause with even small rises of room temperature. it is. Its critical temperature (the temperature above which the
Therefore, desflurane uses the Ohmeda TEC6 vaporizers with a substance cannot be liquified no matter how much pressure has
heating element to maintain a temperature of 39
C. This gives a been applied) is 36.5
C (above room temperature). When nitrous
stable SVP of 200kPa, which allows an accurate concentration of oxide is used, the vapour is released first from the cylinder, and
desflurane to be administered to the patient with varying con- then liquid inside the cylinder vaporizes to replace what has been
ditions in theatre. used. Therefore, the pressure in the cylinder remains constant
The latent heat of vaporization is an issue which is compen- until the liquid has all been used.1
sated for in vaporizers. It is defined as the energy needed to Use of nitrous oxide has numerous potential side effects.1
convert a substance from a liquid to a gaseous state. This energy  Nausea due to bowel distention and opioid receptor
is taken from surroundings, including the vaporizer itself. As a activation.
result, the vaporizer gets colder as more liquid vaporizes. If this  Diffusion into air filled cavities. It has a high diffusion
was not compensated for, the agent’s SVP would drop, reducing capacity which means it quickly enters cavities such as the
the concentration of volatile released from the vaporizer. There lungs (causing a pneumothorax to expand) or the middle
are various temperature-controlled valves which alter the ratio of ear (which can cause damage after inner ear surgery).
gas split between the bypass and vapour chamber when the  Bone marrow suppression and neurotoxicity. The cobalt
temperature does change, to prevent any fluctuations in anaes- ion in vitamin B12 is oxidized by nitrous oxide and is
thetic delivery. These include bimetallic strips with two metals of therefore unable to be used as a co-factor for methionine
different expansion coefficients, altering the shape of the strip synthetase. This can cause megaloblastic anaemia and
allows changes to the split of gas between the chambers, or agranulocytosis by preventing tetrahydrofolate production.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 23:1 67 Ó 2021 Published by Elsevier Ltd.
 PHARMACOLOGY

Prolonged exposure causes a neurological condition like A GWP depends on two factors. The first factor is the way the
subacute combined degeneration of the cord by prevention gas changes the solar energy irradiance on the earth’s atmo-
of myelin production. sphere with a change in its concentration. The second is the at-
 Teratogenic e proven only in rat models. mospheric lifetime of the gas, which depends on how quickly it is
 Diffusion hypoxia can occur on waking. This phenomenon broken down and is determined by its chemical structure. CeF is
is due to the concentration effect happening in reverse. The the strongest bond (followed by CeH, CeCl and CeBr), so at-
volume of nitrous oxide entering the alveolus from the mospheric OH displaces F less easily. Therefore, the different
blood is greater than the amount of nitrogen entering the agents have differing atmospheric lifespans. The IPCC (the
pulmonary circulation. Therefore, the alveolar gases are leading authority on climate change) uses the GWP100, which is
therefore diluted, but using 100% oxygen on waking pre- the GWP over 100 years to compare the long-term effects of the
vents the hypoxia occurring. agents.
 It can induce respiratory depression by reducing tidal Carbon dioxide has a GWP100 of 1, and carbon dioxide
volume and reduce cardiac contractility with a mild direct equivalency (CO2e) is used as the reference for other gases
effect. relative to CO2. Anaesthetic gases have 100e1000 times higher
 Release of nitrous oxide contributes to global warming. warming potential than carbon dioxide. The GWP100 of des-
 Increases pulmonary vascular resistance-caution in pul- flurane is 2540, sevoflurane is 130, isoflurane is 510, and nitrous
monary hypertension. oxide is 265. Obtaining a MAC of 1.0 over a period of 1 hour at
 Increases cerebral metabolic rate, cerebral blood flow and 1 L/min fresh gas flow is equivalent to driving 4 miles in a car
consequently intracranial pressure. using sevoflurane, 8 miles with isoflurane and a massive 190
The concentration and second gas effect have been described miles with desflurane. It is also worth noting that using N2O with
earlier in the article. sevoflurane leads to a significant worsening of the effect on the
carbon footprint with your anaesthetic. A MAC of 0.6 N2O, with a
Xenon 0.4 MAC of sevoflurane, over 1 hour with fresh gas flows of
1 L/min is equivalent to driving 62 miles.7
Xenon is an inert and odourless gas which has a very fast onset
Therefore, the most important measures to reduce the carbon
and offset of anaesthesia due to its low blood:gas partition co-
footprint of an anaesthetic is to avoid desflurane and nitrous
efficient. It is extremely expensive to produce by fractional
oxide, use low flows on the anaesthetic machine and use regional
distillation of air and anaesthetic equipment is rarely calibrated
for xenon, which both limit its usage. It is not metabolized and is
or total intravenous anaesthetic if you are able. A
excreted unchanged via the lungs. It is non-toxic, not flammable,
and is non-irritant to the airway.
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imal respiratory effects (slows respiratory rate slightly, but
II: inhalation anaesthetic agents. Cont Educ Anaesth Crit Care Pain
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ANAESTHESIA AND INTENSIVE CARE MEDICINE 23:1 68 Ó 2021 Published by Elsevier Ltd.