20.

INHALATIONAL ANAESTHETIC AGENTS

Inhalational anaesthesia forms the basis of most general anaesthetics. The exact mechanism
of action for inhaled anaesthetics is unclear however inhaled anaesthetics are known to
augment inhibitory CNS signals including chloride channels (GABA receptors) and potassium
channels while depressing excitatory neurotransmission in Ach, glutamate and serotonin
pathways. In resource rich countries, where ultra-short acting intravenous anaesthetic drugs
and computer delivery systems are available, some anaesthesia providers favour total
intravenous anaesthesia (TIVA).

The inhalational anaesthetic agents include the gases nitrous oxide (laughing gas), xenon
and cyclopropane and the volatile agents such as ether, chloroform, halothane, isoflurane,
enflurane, methoxyflurane, sevoflurane, desflurane, and trichloroethylene (trilene). The
volatile anaesthetics are liquids at room temperature and require the use of calibrated
vaporizers for inhalational administration. Nitrous oxide, isoflurane and halothane are all
essential medicines of the WHO.

There are two methods to deliver volatile anaesthetic drugs: drawover and continuous flow.
In a drawover system the carrier gases (air or air enriched with oxygen) is drawn through a
low resistance vaporiser by the patient’s inspiratory effort (or by manual ventilation with a
self-inflating bag). The drawover apparatus is robust, compact, portable, cheap and not
dependent on compressed gases. During anaesthesia with continuous flow, compressed
gases at high-pressure first pass through regulators that reduce the gas pressure, then
through flow meters and finally through a vaporiser. Continuous flow apparatus is
dependent on a supply of compressed gas. 

Anaesthesia can be induced intravenously and maintained with a volatile anaesthetic agent
or a volatile anaesthetic agent can be used for both induction and maintenance of
anaesthesia. Inhalational induction of anaesthesia may be a good option for children and
patients who may be difficult to intubate.

The patient may breathe spontaneously or may be paralysed with muscle relaxants. When
muscle relaxants are used, the inspired concentration of volatile anaesthetic agents should
be reduced. Spontaneous ventilation with a volatile anaesthetic agent has greater safety.
The patient will adjust their own dose. If the anaesthetic is “light” the patient will increase
their respiratory rate and deepen their anaesthetic. If the anaesthetic is “heavy”, respiratory
depression will occur and the patient will inhale less anaesthetic.

Ether, which is both an anaesthetic and analgesic, may be used as the only anaesthetic drug
or combined with other drugs. Halothane and similar volatile anaesthetics are not
analgesics. 

Pharmacokinetics

An inhaled anaesthetic agent will first enter the alveoli, then the blood. The circulation will
carry the agent to all the organs of the body including the brain. It is the partial pressure of
the inhalation anaesthetic agent in the brain that causes anaesthesia. At equilibrium, the
partial pressure of the gases in the alveoli will be equivalent with the partial pressures in the
patient’s blood and brain. During induction of anaesthesia, the anaesthesia provider aims to
quickly achieve at least a minimum alveolar concentration (MAC)  while avoiding the
deleterious effects of overly deep anaesthesia. There are many factors that determine the
speed of onset of an inhaled anaesthetic agent including the inspired concentration,
alveolar ventilation, agent solubility and the mechanics of the breathing system.

The higher the alveolar ventilation, the more inhaled anaesthetic agent will be taken into
the lungs and the quicker the rise in the partial pressure of the agent in the brain. The
higher the inspired concentration of the agent the more rapid the rise in the partial pressure
in the brain. A common strategy is to initiate inhaled anaesthetic delivery with moderate to
high fresh gas flows (≥6 L/min) and moderate “overpressure” (≥2 × MAC) and reduce the
inspired concentration once the target level is reached or slightly exceeded. Complete
equilibration with any tissue takes 3 time constants. The brain time constant for isoflurane is
3-4 minutes and  for sevoflurane, desflurane, or nitrous oxide is ~ 2 minutes. For all inhaled
anaesthetics, the inspired concentration should therefore be decreased to a maintenance
concentration after 6-12 minutes.

Agents with a low boiling point will evaporate easily (are more volatile) and therefore can be
delivered in higher concentrations. Ether has a boiling point of 35 degrees Celsius and could
produce a maximum concentration of 56%. Another way of expressing volatility is the
saturated vapour pressure (SVP). The SVP is the pressure exerted by the vapour phase of an
agent when in equilibrium with the liquid phase. The SVP of ether is 425 mmHg (59 kPa).
The SVP of halothane (243 mmHg) and isoflurane (250 mmHg) are similar. Sevoflurane has
an SVP of 160 mmHg.
The greater the solubility of the gas in the blood, the slower the rise in the partial pressure
of the agent in the brain and therefore the slower the onset of anaesthesia. A very soluble
agent such as ether will dissolve in large quantities in blood before the brain levels rise
enough to cause anaesthesia. More soluble agents will also have longer recovery. The
solubility of an agent is called its blood-gas partition coefficient. The blood-gas coefficient is
the ratio of the amount dissolved in blood to the amount in the same volume of gas in
contact with that blood. Ether is very soluble and has a blood gas coefficient of 12.
Halothane with a blood gas coefficient of 2.3 has a much more rapid onset of anaesthesia
than ether, however slower than isoflurane (blood gas coefficient 1.4) and sevoflurane
(blood gas coefficient 0.69).

Inhalation agents also vary in their potency. The minimum alveolar concentration (MAC) is
used to express the potency of inhalation agents. The MAC is the minimum alveolar
concentration, at 1 atmosphere, of an agent required to prevent a response to a skin
incision in 50% of patients. The lower the MAC the more potent the agent. The MAC of an
agent may be reduced (potency increased) by many factors including combining other
central nervous system depressants, hypothermia, severe hypotension and extremes of age.
The MAC of an agent can be increased (potency reduced) by factors such as hyperthermia,
hyperthyroidism and alcoholism. Halothane has high potency (MAC 0.75%), isoflurane has a
lower potency (MAC 1.3%) and sevoflurane has an even lower potency (MAC 2.4%). MAC
awake is the expired concentration at which 50% of patients respond to voice or a non-
noxious tactile stimulus. MAC awake is usually approximately 40% of MAC.
The anaesthesia provider can predict the behaviour of a volatile anaesthetic agent from the
SVP, blood gas coefficient and MAC. Ether is highly soluble (Blood-gas coefficient 12) and
will have a slow onset. With a MAC of 1.92% it has low potency but fortunately has an SVP
of 425 mmHg, which means that it can be given in high concentrations. Trichloroethylene is
potent (MAC 0.17%) but is a weak anaesthetic because vaporisers cannot produce high
enough concentrations because the volatility is very low (SVP 60 mmHg). It has a high blood
solubility (blood-gas coefficient 9) so has a slow onset. Halothane is volatile (SVP 243 mmHg)
so adequate concentrations can be delivered by a vaporiser. The solubility is low (blood gas
coefficient 2.3), allowing rapid induction and recovery.

Pharmacodynamics

The effect of volatile anaesthetic agents on other organs are usually similar, however, there
are some important differences. Isoflurane, sevoflurane and desflurane all decrease blood
pressure by decreasing SVR but preserve CO. Halothane causes a dose dependent decrease
in CO. Sevoflurane may prolong the QT interval. All common volatile agents reduce TV but
the concomitant increase in RR does not compensate, resulting in a reduction in minute
ventilation. Isoflurane and sevoflurane decrease airway resistance. Desflurane and
isoflurane may irritate the airway of severe asthmatics resulting in
laryngospasm/bronchospasm. All volatile inhalation agents decrease cerebral metabolic
rate, decrease oxygen consumption and cause vasodilation of cerebral vessels (with the
potential to increase intracranial pressure). The most common adverse effect of inhaled
anaesthetic agents is PONV. Hepatotoxicity and hepatic failure is a rare association with
halothane. All of the current volatile agents may trigger malignant hyperthermia (MH).
Patients susceptible to MH may have inheritable alterations in proteins that modulate
muscular cytosolic calcium concentrations. Symptoms of this hypermetabolic process
include muscle rigidity, hyperthermia, rapid onset tachycardia, hypercapnia, hyperkalaemia,
and metabolic acidosis.

Halothane

Halothane, 2-bromo-2-chloro trifluoroethane is a colourless, pleasant smelling, light

sensitive hydrocarbon anaesthetic agent first synthesised by Charles Suckling of Imperial
Chemical Industries (ICI) in 1951 and first administered by Dr Michael Johnstone in 1956.
Halothane rapidly replaced the flammable ether and cyclopropane and became the principal
inhalation agent for millions of anaesthetics but has now been discontinued in most
resource rich countries, replaced by sevoflurane and desflurane. However, halothane
remains on the WHO list of essential drugs and is widely used in many countries 

Halothane is chemically unstable, decomposing to HBr, HCl and phosgene on exposure to

light. To prevent degradation, 0.1% thymol is added to halothane. A yellow tinge to the
halothane solution implies a thymol build-up which will eventually clog the vaporiser. Of
practical importance, halothane will erode aluminium, brass, lead (older EMO) and rubber.
Never connect any vaporiser containing halothane to the inlet port of an EMO (Epstein,
Macintosh, Oxford) vaporiser. 
Halothane is potent and overdose is easy. Safe administration requires an understanding of
its pharmacodynamics/pharmacokinetics and vigilance. Halothane must always be given
through a calibrated vaporiser. Using a vaporiser not made for halothane will give an
incorrect concentration. If halothane is put into a vaporiser calibrated for a more volatile
agent, the effect will be a lower concentration. If halothane is put into a vaporiser calibrated
for a less volatile (e.g. sevoflurane), the effect will be a higher concentration. A
representative vaporiser splitting ratio at 1% for halothane is 46:1 and for sevoflurane is
25:1. At a dialled 1% this sevoflurane vaporiser would be delivering 1.8% halothane (46/25 X
1%). At 3% the splitting ratios become 14:1 and 7:1 giving a delivered halothane
concentration of 6%. If the sevoflurane vaporiser was turned to 8% it could deliver in excess
of 16% halothane - a rapidly lethal dose. Be alert that Tec 3, 5 & 7 vaporisers can deliver 5%
halothane i.e. 6.5MAC 

Halothane will cause dose-dependent respiratory depression resulting in hypoxia. Halothane

produces dose-dependent increases in the rate of breathing. 1 MAC of halothane will
approximately double the respiratory rate; however, tidal volume is decreased. The patient
will have rapid shallow breathing. The increase in the rate of breathing is insufficient to
offset the reduction in tidal volume, causing a reduction in minute ventilation and elevation
of arterial carbon dioxide (PaCO2). Halothane depresses the ventilatory response to arterial
hypoxia that is normally mediated by the carotid bodies. 1.1 MAC will produce 100%
depression. Oxygen must be provided for halothane anaesthesia.

Halothane produces dose dependent cardiovascular depression. 1 MAC of halothane can

cause a 20% reduction in blood pressure as a consequence of decreases in myocardial
contractility and cardiac output (decrease in stroke volume). Peripheral vascular resistance
is not significantly altered by halothane. Halothane slows conduction of cardiac impulses
through the atrioventricular node and the His-Purkinje system. A junctional rhythm causing
a fall in blood pressure is common. Halothane also reduces the dose of adrenaline
(epinephrine) required to produce ventricular arrhythmias. The dose of submucosally
injected adrenaline necessary to produce ventricular arrhythmias in 50% of patients
receiving 1.25 MAC of halothane is 2.1 micrograms/kg. It is likely that cardiac dysrhythmias
due to adrenaline will persist until the halothane concentration is less than 0.5%. Injection
of adrenaline by the surgeon may be dangerous and the doses, and the patient, need to be
carefully monitored. Traditionally, adrenaline doses are recommended to be of
concentrations less than 1:100,000 (1 mg/100ml) with a total dose of less than 0.1 mg in 10
minutes and less than 0.3 mg in an hour.

Halothane will cause uterine relaxation. This may be useful to help manual removal of the
placenta but can cause increased uterine haemorrhage when given in concentrations above
0.8%. 0.5 MAC of halothane with 50% nitrous oxide will ensure amnesia during caesarean
section and has no effect on the foetus (Umbilical vein to maternal vein ratio 0.6) and does
not increase uterine bleeding. 

Halothane undergoes 25 % hepatic metabolism via cytochrome P450 systems. The major
metabolite is trifluoroacetic acid, which can induce a T-cell mediated immune response
resulting  in hepatitis. Halothane hepatitis may range from mild to fulminant hepatic
necrosis and possibly death. Fatal hepatic necrosis is rare, estimated at 1 in 5000 to 35000
anaesthetics. 

Inhalational induction requires the gradual increase of inspired concentration up to 3%. A

maintenance dose is 1 to 2% for spontaneously breathing patients and 0.5 to 1% during
IPPV. Recovery is quick though slower than sevoflurane. 

Isoflurane

Isoflurane, 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether, has an SVP of 250 mmHg,

blood gas coefficient of 1.4 and MAC of 1.15. It is a clear colourless stable liquid with a fast
recovery but is a difficult agent to use for inhalation induction because of its irritating
noxious smell.
Isoflurane does not sensitise the heart to adrenaline. It causes a dose-dependent fall in
blood pressure comparable with halothane but in contrast cardiac output is well
maintained, the decrease in blood pressure being due to vasodilatation. Isoflurane does not
affect ventricular conduction and does not increase the excitability of ventricular
myocardium. Respiration is depressed in a dose-dependent fashion approximately
equivalent to halothane. (1 MAC PaCO2 < 50 mmHg). The time to emergence after
prolonged anaesthesia is approximately 12 minutes. The high molecular stability of
isoflurane results in metabolism of less than 0.2% of the inspired dose.

Sevoflurane

Sevoflurane is a fluorinated methyl isopropyl ether. It is sweet smelling and minimally

pungent, and hence well suited to inhalational inductions.
Sevoflurane has an SVP of 160 mmHg, blood gas coefficient of 0.6 and MAC of 2.0. It is
sweet smelling and non-irritant. A desirable characteristic of sevoflurane is faster induction
and awakening compared with all other volatile anaesthetic agents except desflurane.
Sevoflurane induces a dose-dependent reduction in blood pressure primarily through the
reduction of systemic vascular resistance. At clinically relevant concentrations, cardiac
output  is usually preserved. Coronary blood flow remains preserved and regional blood
flow to other vascular beds appears to be maintained at least when systemic
haemodynamics are preserved. Like all other modern volatile anaesthetics, sevoflurane
results in bronchodilation, blunting of the hypoxia/hypercapnia ventilatory response, and
inhibition of hypoxic pulmonary vasoconstriction. Sevoflurane is a cerebral vasodilator.

In young children, anaesthesia with sevoflurane has been shown to be accompanied by

behavioural changes during recovery known as emergence agitation (10-80%). EA is
characterized by a period of restlessness, agitation, inconsolable crying, disorientation,
delusions and occasionally combativeness. An episode of EA may last 20 to 30 minutes and
may not respond to routine comforting measures. Unrecognised postoperative pain is likely
the single most common cause of emergence agitation in all groups. Treatment of ongoing
delirium has not been widely studied, but current strategies include propofol 1 to 3 mg/kg
IV, fentanyl1 to 2 µg/kg, or dexmedetomidine 0.3 µg/kg.
The interaction of sevoflurane with carbon dioxide absorbents leads to the formation of
several products including Compound A (trifluoromethyl vinyl). Though compound A causes
renal injury in rodents, significant renal toxicity has not been associated with sevoflurane in
humans.

Enflurane

Enflurane is similar to halothane. It is a colourless volatile liquid with an SVP of 175 mmHg,
blood gas coefficient of 1.9 and MAC of 1.7. Enflurane’s usage has declined in favour of
newer halogenated anaesthetics such as isoflurane sevoflurane, and desflurane which show
a better pharmacokinetic profile (faster induction and emergence times) and less side
effects, compared to enflurane, especially in terms of nephrotoxicity and proconvulsant
activity. Enflurane causes less sensitisation of the heart to adrenaline than halothane and a
greater fall in blood pressure but a similar fall in cardiac output. The rise in cerebral blood
flow (and intracranial pressure) is less than with halothane but enflurane can produce
epileptic waveforms on EEG, especially above 2 MAC and if PaCO2 is less than 30 mmHg.
20% of enflurane is metabolised, producing fluoride ions. Peak fluoride ion concentration
after prolonged enflurane administration (2.5 MAC hours) may reach 20 µM/l (1/3 the level
considered to be toxic).

Diethyl ether (Ether).

Ether is an inexpensive, colourless agent made from sugar cane with a strong irritant smell.
It was used in the “first anaesthetic” (W.T.G. Morton, Boston, 16 October 1846). Ether has
some significant advantages. It is both an anaesthetic and analgesic and is inexpensive.
Unlike other volatile agents, ether stimulates cardiac output (maintaining blood pressure)
and respiration. (Ether is safe to use for spontaneous respiration without additional oxygen
for most patients and is an excellent inhalation agent where oxygen is unavailable). Very
high concentrations of ether may cause direct myocardial depression. Ether does not relax
the uterus unlike halothane and some other volatile agents but gives good abdominal
muscle relaxation. It is a good bronchodilator. 10 to 15% is metabolised. It should be stored
in a cool dark place.

Though ether can be used as a sole anaesthetic agent, as it is both an anaesthetic and
analgesic, it has several properties that make it less than ideal. Inhalational induction by
ether is very difficult because it has an unpleasant smell, is very slow, causes marked
secretions (requiring atropine premedication), bronchial irritation, breath holding and
coughing. Ether may cause postoperative nausea and vomiting (PONV) and recovery is slow.
It is also flammable in air and explosive in oxygen and nitrous oxide.

Intravenous induction or using halothane for induction and then changing over to ether may
overcome problems with ether inhalational induction. For intravenous induction the patient
should be premedicated with atropine, pre-oxygenated, induced with thiopentone and
intubated after receiving a muscle relaxant. Ether in air is delivered by intermittent positive
pressure ventilation (IPPV) at 10 to 15% for about 2 to 8 minutes, then reduced to 4 to 8%
depending on the patient’s need (sick patients may only require 2%). Patients who are
spontaneously breathing after suxamethonium will require a higher maintenance
concentration of ether (6 to 8%). Stop the ether well before the end of the operation to
avoid prolonged recovery.

Ether is flammable in air and explosive in oxygen and nitrous oxide. The safest practice is to
not use ether with diathermy. The ether vapour is flammable within the patient (airway,
lung or stomach) and within 30 cm of the anaesthetic circuit. No sources of ignition are
permitted within 30 cm of this zone of risk. Scavenging must always be carried out if
possible. If diathermy must be used with ether, oxygen must be turned off well beforehand. 

Trichloroethylene

Trichloroethylene is a colourless, non-irritant, safe agent that is decomposed by light. It

maintains cardiac output and provides good analgesia but it cannot be used as a sole
anaesthetic agent. Trichloroethylene has an SVP of 60 mmHg so it is impossible to deliver a
high enough concentration to cause anaesthesia. A blood/gas coefficient of 9 means that
induction and recovery is slow (turn off at least 10 minutes before the end of anaesthesia).
Higher concentrations of trichloroethylene can cause arrhythmias and adrenaline should not
be administered with trichloroethylene. Trichloroethylene causes an increase in respiratory
rate but a decrease in tidal volume so that PaCO2 rises and PaO2 falls in spontaneously
breathing patients. It is a poor muscle relaxant and causes more PONV than halothane.
Trichloroethylene must never be used in a circle system with soda lime as the toxic
compounds phosgene and carbon monoxide are produced.

Trichloroethylene is an excellent agent to use as background analgesia. Initial dose is 0.5 to

1%, reducing to 0.2 to 0.5%. 

Methoxyflurane

Methoxyflurane is a potent (MAC 0.2) anaesthetic and powerful analgesic but with very slow
onset and recovery (blood gas coefficient 13). The very low SVP (23 mmHg) of
methoxyflurane made it difficult to vaporise. The metabolism of methoxyflurane releases
fluoride ions. High fluoride levels (> 50μmol/l) is associated with polyuric renal failure.

Cyclopropane

Cyclopropane has fast onset and recovery (blood gas coefficient 0.45). It causes marked
respiratory depression and ventricular arrhythmias are common with hypercapnia,
hypoxaemia and atropine or adrenaline administration. Nausea and vomiting are common.
Cyclopropane was employed extensively throughout the 1930s, 1940s and 1950s, however
it is highly explosive in oxygen and air.

Nitrous Oxide

Nitrous oxide (N2O) is a colourless, sweet smelling, non-irritant and non-flammable gas. It is
a fair analgesic and has minimal cardiovascular and respiratory effects. It is stored in a
cylinder, compressed as a liquid/vapour below its critical temperature (36.5°C). N2O has a
rapid onset and recovery (blood gas coefficient 0.47) but is a very poor anaesthetic (MAC
104%). 

There are several disadvantages. N2O is relatively expensive, does not produce muscle
relaxation, increases cerebral blood flow and may increase pulmonary vascular resistance.
N2O is unique in its ability to inhibit methionine synthase oxidation by oxidizing a cofactor,
vitamin B12. Reduced methionine synthetase activity may also lead to haematological
complications such as megaloblastic anaemia and myelinopathies associated with subacute
combined degeneration of the spinal cord.

Nitrous oxide has a 35-fold greater blood gas coefficient than nitrogen (0.013). For every
molecule of nitrogen removed from airspace, 35 molecules of nitrous oxide will pass in.
During anaesthesia, nitrous oxide diffuses into any body cavity, which contains air. This
includes the middle ear, gut and a pneumothorax. 500% N2O will double the size of a
pneumothorax in 10 minutes. 

Nitrous oxide may speed the onset of volatile agents by the ‘second gas effect’. N2O
transfers across the alveolus rapidly because of its high lipid solubility. This leads to
concentration of the remaining gases in the alveolus (volatile agent, oxygen, and nitrogen),
increasing the driving pressure of volatile anaesthetic agents into the blood. Similarly, N2O
can cause diffusion hypoxia. (At the end of an operation nitrous oxide rapidly leaves the
blood and passes out though the lungs. This can dilute the oxygen in the lungs). All patients
should receive oxygen at the end of the anaesthetic. 

Nitrous oxide can be used as a simple analgesic for mild to moderate pain. It may be used in
combination with oxygen and another volatile anaesthetic for the maintenance of
anaesthesia. 

  Agent     Blood Gas        SVP mmHg   BP     MAC

    Coefficient
    (kPa)
Ether 12 425 (59) 35 1.9

Halothane 2.4 243 (32) 50 0.76

Enflurane 1.9 175 (24) 56 1.68

Isoflurane 1.4 250 (33) 49 1.3

Sevoflurane 0.69 160 (21) 58 2.4

Nitrous oxide 0.47 -88 105

Desflurane 0.42 673 (88) 23 6

Trichloroethylen 9 60 (8) 87 0.17
e

Methoxyflurane 13 23 (3) 105 0.2

Cyclopropane 0.45 -33 9.2