Br. J. Anaesth.
(1981), 53, lIS
CHLOROFORM IN CLINICAL ANAESTHESIA
J. P.
Chloroform probably has aroused more contro-
versy than any other anaesthetic agent. Even today
there are anaesthetists who would regard its use as
bordering on the irresponsible, while others have
used chloroform throughout their professional
lives without mishap.
Chloroform was first used for clinical anaes-
thesia in November 1847 by James Y. Simpson,
Professor of Midwifery in the University of
Edinburgh at the instigation of David Waldie, a
Liverpool chemist. In March of that year, M. J. P.
Flourens had described its use for anaesthesia in
lower animals in a paper addressed to the
Academic des Sciences in Paris, but expressed the
view that it was unsuitable for clinical use.
Simpson had previously used ether to relieve the
pains of labour in childbirth, but was dissatisfied
with that agent because of the technical difficulties
involved in its administration and the frequency of
nausea and vomiting associated with its use.
Simpson's success with chloroform was im-
mediate and its advantages were so apparent that,
with the ardent support of the Professor of
Surgery, James Syme, its use was extended to
general surgery throughout the Royal Infirmary of
Edinburgh and soon it surpassed ether in popu-
larity, a rivalry that was to continue into the 20th
century and to polarize into the Edinburgh and
London Schools of Anaesthesia. In Edinburgh
and in Scotland generally the claims of chloroform
were upheld, whereas the London School gave its
allegiance to ether, and the arguments about the
relative merits of the two drugs were thrashed out
at meetings of the Physiological Society and the
Royal Society, among others, and even in Special
Commissions, for about the next 100 years. Indeed
it could be claimed that they have not stopped yet.
Although the use of chloroform was accepted
readily to provide anaesthesia for surgical pro-
J. P. PAYNE, M.B., F.F.A.R.C.S., D.A., Research Department of cidentally with or even before respiratory arrest if
Anaesthetics, Royal ~ollege of Surgeons of England, 35/43
Lincoln's Inn Fields, London WC2A 3PN; and The
Anaesthetics Unit, The London Hospital Medical College, form. On this basis he set about designing an
Turner Street, London El 2AD.
0007--{)912/81/130011-o5 $01.00
PAYNE
cedures, Simpson ran into trouble in his use of
chloroform to relieve pain during childbirth. His
advocacy of chloroform for this purpose stirred
deep emotions and aroused bitter opposition,
particularly amongst the clergy of the established
church. The ministers and elders of the church,
none of whom was likely to suffer the pains of
labour, accused Simpson of arrogance in attempt-
ing to thwart what had been ordained by God. In
defence of their case they quoted the Biblical text
"In sorrow shalt thou bring forth children"
(Genesis 3:16). Simpson, however, also knew his
Bible and he retorted with the text "And the Lord
God caused a deep sleep to fall upon Adam; and he
slept; and he took one of his ribs and closed up the
flesh instead thereof' (Genesis 2: 21). This par-
ticular controversy was brought to a rather abrupt
end in 1853 when Queen Victoria summoned John
Snow to the Palace to give her chloroform for the
birth of Prince Leopold. When the Queen of
England was willing to accept the benefits of
chloroform, who would deny her!
The first recorded death under chloroform
occurred on January 28, 1848 when a 15-yr-old girl,
Hannah Greener of Winlaton in County Durham,
died suddenly just as the surgeon was about to
remove an in-growing toe-nail. This dangerous
ability of chloroform to cause sudden death,
although rare, usually occurred during light anaes-
thesia, while deep anaesthesia appeared to provide
protection. What was worse, those who died were
often healthy patients undergoing relatively minor
surgical procedures. Simpson was convinced that
this problem could be overcome by a proper
attention to respiration and by the rapid induction
of deep anaesthesia. John Snow was less convinced
'and adopted a more scientific approach, whereby
he investigated the concentration of inhaled
chloroform associated with cardiac arrest and
demonstrated that such arrest occurred coin-
the inhaled concentration reached 8-10% chloro-
appropriate vaporizer to deliver known concen-
'© Macmillan Publishers Ltd 1981
12S
trations of chloroform up to a maximum of 4%. To
do this, certain physical characteristics of the drug
needed to be known, and this explains why the
physical properties of chloroform were investi-
gated thoroughly at such an early stage.
The principal method for the preparation of
anaesthetic chloroform involves the, chlorination
of acetone or acetaldehyde by calcium hypo-
chlorite to produce a clear colourless liquid with a
sweetish rather pleasant taste and smell.
Chloroform has a boiling point of 61.2°C, a
specific gravity of 1.49 and a saturated vapour
pressure of 160 mm Hg. These physical charac-
teristics fall within the range regarded as highly
suitable for a volatile inhalation agent and John
Snow made good use of them in the design of his
vaporizer which was to become the model for
much more sophisticated vaporizers up to the
present day.
The belief that the strength of the chloroform
vapour reaching the patient was vitally important
led to the development of a range of vaporizers and
inhalers. Perhaps the most ingenious and certainly
the simplest was Rowling's percentage chloroform
bottle (Nosworthy, 1973), the design of which
depends on the fact that when chloroform and
liquid paraffin were mixed the specific gravity of
the mixture decreased as the chloroform evap-
orated. The bottle provided a concentration range
from 3.5 to 2%. Two later developments, the
Junkers inhaler and the Vernon Harcourt inhaler
(Thomas, 1975) were probably the most popular of
all and survived well into the present century.
Indeed, Junkers inhalers were still being used in
some parts of the world after the end ofthe Second
World War.
Although an association between chloroform
and sudden death on the operating table was
recognized very soon after the drug was intro-
duced, more than 60 yr were to elapse before
ventricular fibrillation was identified as the main
cause. At first sight this may seem remarkable, but
a number of factors contributed to this situation.
First, Simpson's prestige and his insistence that
the cause of death was respiratory failure initially
distracted attention from the effect of chloroform
on the heart and this interpretation was reinforced
by the activities of Simpson's disciple, Surgeon-
Major Edward Lawrie of the Bengal Medical
Service. Lawrie was a forceful, stubborn, not to
say bigoted, character who was utterly convinced
that chloroform had no harmful effects on the
BRITISH JOURNAL OF ANAESTHESIA
heart, and he persuaded the Nizam of Hyderabad
to finance experiments which he conducted to
prove his contention. It was perhaps unfortunate
that Lawrie chose as his experimental animal the
dog, which is remarkably resistant to the effects
of chloroform, because his results merely
strengthened his prejudices and enabled him to
convince many, who should have known better, of
the validity of his arguments. The story of the
Hyderabad Commissions and the associated con-
troversy have been described by Thomas (1974).
Another factor that added to the confusion was the
fact that respiratory failure was undoubtedly one
cause of death during chloroform anaesthesia. It is
clear from examination of available case records
that many deaths were a result of asphyxia from
respiratory obstruction, overdose or the inhalation
of vomitus.
The definitive experiments that established
ventricular fibrillation as a principal danger of
chloroform administration were carried out by
Levy (1912a) who showed that, when cats breath-
ed chloroform 0.5% in air, stimulation of the right
cardio-accelerator nerve led to ventricular fibril-
lation and cardiac arrest, but that risk was substan-
tially diminished when the inspired chloro-
form concentration was 2% or more (Levy,
1912b). Earlier, Levy (1911) had demonstrated
that the i.v, injection of adrenaline 0.03 mg in
1 : 20 000 solution to cats lightly anaesthetized with
chloroform almost invariably induced ventricular
fibrillation, whereas full chloroform anaesthesia
provided protection. The implication of these
observations was that ventricular fibrillation and
cardiac arrest were associated with some form of
sympathetic stimulation, a conclusion in keeping
with both experimental and clinical evidence ac-
cumulated over the years.
The association of ventricular irregularities
with light chloroform anaesthesia is now well
documented. As long ago as 1893 Kirk observed
that cardiac arrhythmias tended to develop in
patients after the chloroform had been withdrawn,
an observation confirmed by Payne and Conway in
1963. Earlier Hill (1932a) had emphasized that
ventricular irregularities often developed just after
induction ofanaesthesia and that overdose was not
a factor in their production. In a previous paper
the same author (Hill, 1932b) argued that ven-
tricular extrasystoles were not dangerous in them-
selves, but their importance lay in the ease with
which they could lead to ventricular fibrillation.
CHLOROFORM IN CLINICAL ANAESTHESIA 13S

There is now substantial evidence to show that procedures breathing is quiet and unobtrusive and
ventricular extrasystoles can result from specific the marked tachypnoea seen often with tri-
stimuli such as the i.v, injection of atropine, the chloroethylene and halothane does not occur,
manipulation of certain organs or tumours and the although a respiratory rate of around 30 b.p.m. is
retention of carbon dioxide, all of which give rise not uncommon especially when the blood concent-
to sympathetic overactivity. Such extrasystoles rations ofchloroform are high. The increase in rate
can be abolished by the deliberate suppression of is usually associated with some reduction in tidal
sympathetic influence by activating the para- volume but, overall, the minute volume is not
sympathetic nervous system either through the substantially reduced unless morphine premedi-
action of ether on the pulmocardiac reflex cation has been used; only rarely is there a
(Johnstone, 1952) or by the use of ~-receptor significant increase in carbon dioxide retention.
blocking agents (Payne and Senfield , 1964). Oxygen consumption during chloroform anaes-
Excessive vagal activity can, of course, produce its thesia decreases to substantially the same value as
own problems and bradycardia associated with during natural sleep, as occurs with other general
nodal rhythm, a low pulse pressure and hypoten- anaesthetics, a decrease which reflects merely the
sion is not uncommon during general anaesthesia reduced tissue requirements for oxygen during
with any agent, and chloroform is no exception. anaesthesia.
Fortunately, this combination of effects responds During chloroform anaesthesia, spontaneous
to atropine. breathing is usual either through a Magill attach-
Conversely the depression of vagal activity often ment with a higher gas flow (8-12 litre min - 1) and
will provoke ventricular arrhythmias and for this a calibrated'vaporizer or alternatively, a closed
reason Levy (1922) advised against the use of circle system with a vaporizer included in the circle
atropine as premedication before chloroform may be used. The practice of using nitrous oxide as
anaesthesia. He argued that vagal activity was a carrier gas dies hard, but there is force in the
necessary to control cardiac irritability and that argument that oxygen alone should be used with
any decrease was potentially dangerous in the chloroform. It has been known for many years that
presence of chloroform. Convincing proof of this the frequency of jaundice after chloroform anaes-
interpretation was obtained in 1948 when John thesia is significantly less when oxygen rather than
Gillies carried out a survey of more than 800 000 air is utilized as the carrier gas. This knowledge
chloroform anaesthetics and reported that the was placed on a quantitative basis by the work of
frequency of cardiac arrest was twice as great in the Goldschmidt, Ravdin and Lucke (1935), who
group of patients given atropine as in those who showed in experiments in dogs that the frequency
were not given the drug. Gillies postulated that ofliver necrosis after 1 h ofchloroform anaesthesia
protection from vagal reflexes was obtained at the in a semi-closed system was approximately 10
expense of an increased sensitivity of the heart to times greater when the carrier gas was air rather
sympathetic stimulation. than oxygen. On the basis of these and other
Thus the great body of evidence implies that the experiments the protective value of high oxygen
cardiac disturbances seen during chloroform concentrations is not in doubt, but it has to be
anaesthesia reflect an imbalance of autonomic admitted that with oxygen alone the blood con-
activity and are of no greater significance than centrations of chloroform are substantially greater
similar arrhythmias observed during anaesthesia than those needed for anaesthesia when air or a
with any other agent. There is no evidence to combination of nitrous oxide and oxygen is used as
support the alternative suggestion that such car- . 'the carrier gas.
diac disturbances are a result of the direct de- The first detailed study of blood concentrations
pressent effect of chloroform on the heart although of chloroform in man was carried out by Morris
there can be little doubt that, like other volatile (1951), who obtained a mean value of9.2mg dl- 1
anaesthetics given in overdose, chloroform can in patients breathing air, a value substantially less
depress cardiac action. than that of 17.9 mg dl " 1 with a range of
The initial contention that the main problem of 11.05-26.79 mg dl " 1 obtained by Payne and
chloroform was its effect on respiration has not Conway (1963). The discrepancy is perhaps not
withstood. the test of', time. Chloroform has no quite as great as would appear at first sight, since
marked effects on respiration. For most surgical Morris used venous blood samples for his analyses,
14S
whereas the values of Payne and Conway
were derived from arterial samples. Moreover, in
both studies blood samples were taken at random
intervals and almost certainly equilibrium
between arterial blood and venous blood was not
achieved. In a later study (Poobalasingham and
Payne, 1978) a mean chloroform concentration of
17.28 mg dl " I was obtained, corresponding to an
inspired concentration of2.5%. Previously Smith
and his colleagues (1973) reported a mean value of
9.8 mg dl " I, a figure remarkably close to that of
Morris (1951). Smith and his colleagues had used a
50% mixture of nitrous oxide and oxygen sup-
plemented by tubocurarine and assisted venti-
lation and undoubtedly these factors contributed
to their ability to control anaesthesia when the
blood concentrations of chloroform were so small.
This interpretation is supported by the fact that a
similar concentration, 10.14 mg dl- I, was re-
ported by Poobalasingham and Payne for their
series of patients whose lungs were ventilated
using chloroform 1% after neuromuscular block-
ade with curare.
The uptake of chloroform varies according to
whether the patient breathes spontaneously or the
lungs are ventilated artificially. In both groups of
patients the initial uptake is rapid, but when
expressed as a percentage of the equilibrium value,
the arterial concentration increases faster during
controlled ventilation than during normal breath-
ing. In patients breathing spontaneously the
chloroform concentration in arterial blood reaches
about 25% of equilibrium with the inspired
concentration after 1 h of exposure to chloroform,
whereas during artificial ventilation more than
40% of equilibrium is achieved within 1 hand
20% has been reached within 10 min. These
figures have been calculated on the basis of a
chloroform solubility coefficient in blood at 37°C
of 8.4 and an oil-water partition coefficient of 70.
On the assumption that the percentage equili-
brium between the alveolar and pulmonary blood
has become virtually constant after 1 h of chloro-
form anaesthesia, these observations imply that
the rate of increase of the alveolar to inspired
concentration ratio is significantly lower in
patients who breathe normally as compared with
those who are ventilated artificially. The expla-
nation ·lies in the fact that, in spontaneously
breathing patients, the increase in the concen-
tration of chloroform in the blood depresses
breathing sufficiently to decrease the alveolar
BRITISH JOURNAL OF ANAESTHESIA
ventilation. Consequently, the amount of chloro-
form to reach the alveloi is reduced also, with the
result that the uptake ofthe drug by the pulmonary
blood is curtailed. When controlled respiration is
used, however, ventilation is constant, so that the
amount of chloroform vapour that reaches the
alveoli in unit time remains unchanged regardless
of the depth ofanaesthesia, and uptake in the blood
continues steadily as long as the alveoli are per-
fused adequately. The practical significance is that
during controlled ventilation the chloroform con-
centration required is unlikely to exceed 1%
whereas when patients are breathing spon-
taneously, 2-2.5% or even greater may be needed
to achieve satisfactory anaesthesia.
Although an association between liver damage
and chloroform anaesthesia was postulated as early
as 1850, it was 1896 before proper recognition was
given to the importance of liver necrosis as a major
factor in the development of liver damage after
chloroform anaesthesia (Bourne, 1936). This
failure probably reflects the obsession of anaes-
thetists with the cardiac problems of chloroform,
so that other aspects of the drug tended to be
ignored. In the early part of the present century a
series of papers from Guthrie (1903), Stiles and
McDonald (1904) and Bevan and Favill (1905)
defined the problems of chloroform toxicity and,
even at that time, related the development of the
clinical syndrome to the pathological changes to be
found in the liver. More important, it soon became
possible to relate these changes specifically to
chloroform and not to other inhalation agents like
ether. The situation was complicated, however,
because it also became clear that the syndrome was
not dose-related, which at least would have defined
the limits of its use. Further studies established
that hypoxia and malnutrition were potent factors
in determining the frequency and extent of chloro-
form damage to the liver and it was shown that a
diet rich in carbohydrate, premedication with
glucose and the use of oxygen in the administration
ofchloroform provided a high degree of protection
against liver damage. The reasons why such pro-
tection should be provided are not immediately
obvious, but recent work reviewed by Geddes
(1970) has shown that, contrary to previous belief,
a substantial amount of chloroform is metabolized
in the body and, although the exact mechanisms
are not known, the liver has been identified as the
site of biological degradation. It has been sug-
gested that a link exists between the metabolism of
CHLOROFORM IN CLINICAL ANAESTHESIA
chloroform in the liver and the occurrence of
hepatocellular damage.
In a reassessment of chloroform immediately
after the Second World War, Waters (1951) and
his colleagues in Wisconsin carried out a detailed
clinical study of the effects of chloroform in more
than 1000 patients and concluded that chloroform
does not deserve to be abandoned as a general
anaesthetic agent. This conclusion was based on
the fact that the Wisconsin group were unable to
detect any significant difference between the re-
sults obtained with chloroform and those with any
other anaesthetic drug. Admittedly, at that time
neither halothane nor the other newer inhalation
agents had been introduced, but it would be
surprising if any of these later drugs were shown to
be vastly superior to chloroform.
A further reason for the retention of chloroform
as an anaesthetic is that there is a great demand in
many parts of the world for a safe volatile inha-
lation agent which is also cheap, potent, non-
explosive and easily transported and stored. Those
who are familiar with the drug will argue that
chloroform meets these criteria, particularly ifit is
used in the modern fashion using thiopentone to
induce anaesthesia, an established airway and
oxygen as the carrier gas. As with many aspects of
medicine, the ideal is not always possible and many
will find chloroform used as described a good
compromise.
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