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CHLOROFORM IN CLINICAL ANAESTHESIA
Br.
J.
Anaesth. (1981), 53, lIS
CHLOROFORM IN CLINICAL ANAESTHESIA J. P.
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 attempting 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 particular 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 anaesthesia, 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 coinJ. 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 the inhaled concentration reached 8-10% chloroLincoln's Inn Fields, London WC2A 3PN; and The Anaesthetics Unit, The London Hospital Medical College, form. On this basis he set about designing an appropriate vaporizer to deliver known concenTurner Street, London El 2AD.
Chloroform probably has aroused more controversy 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 anaesthesia 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 immediate 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 popularity, 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-
0007--{)912/81/130011-o5 $01.00
'© 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 investigated thoroughly at such an early stage. The principal method for the preparation of anaesthetic chloroform involves the, chlorination of acetone or acetaldehyde by calcium hypochlorite 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 characteristics 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 evaporated. 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 introduced, 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, SurgeonMajor 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 controversy 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 breathed chloroform 0.5% in air, stimulation of the right cardio-accelerator nerve led to ventricular fibrillation and cardiac arrest, but that risk was substantially diminished when the inspired chloroform 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 accumulated 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 ventricular extrasystoles were not dangerous in themselves, 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 tristimuli 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 concentto 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 premediaction 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 anaesExcessive 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. During chloroform anaesthesia, spontaneous Fortunately, this combination of effects responds breathing is usual either through a Magill attachto atropine. 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 anaesinterpretation 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 conactivity 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 deThe 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 than that of 17.9 mg dl " 1 with a range of depress cardiac action. 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 supplemented by tubocurarine and assisted ventilation 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 reported by Poobalasingham and Payne for their series of patients whose lungs were ventilated using chloroform 1% after neuromuscular blockade 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 breathing. 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 equilibrium between the alveolar and pulmonary blood has become virtually constant after 1 h of chloroform 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 explanation ·lies in the fact that, in spontaneously breathing patients, the increase in the concentration of chloroform in the blood depresses breathing sufficiently to decrease the alveolar
BRITISH JOURNAL OF ANAESTHESIA ventilation. Consequently, the amount of chloroform 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 perfused adequately. The practical significance is that during controlled ventilation the chloroform concentration required is unlikely to exceed 1% whereas when patients are breathing spontaneously, 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 anaesthetists 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 chloroform 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 protection 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 suggested 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 results 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 inhalation agent which is also cheap, potent, nonexplosive 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. REFERENCES
Bevan, A. D., and Favill, H. B. (1905). Acid intoxication and late poisonous effects of anesthetics-hepatic toxemia, acute fatty degeneration of the liver following chloroform and ether anesthesia. J.A.M.A., 45, 691. Bourne, W. (196). Anesthetics and liver function. Am. J. Surg., 34,486. Geddes, 1. C. (1970). Metabolism of volatile anaesthetics; in Pharmacology Topics in Anaesthesia (International Anaesthesiology Clinics) (ed. R. Miller), p. 145. Boston: Little, Brown & Co.
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Gillies, J. (1948). Analyses of replies to a questionary on the use of chloroform at the present time. Anaesthesia, 3, 45. Goldschmidt, S., Ravdin, 1. S., and Lucke, B. (1935). The effect of oxygen in the prevention of the liver necrosis produced by volatile anesthetics. Am.J. Med. Sci., 189, 155. Guthrie, L. G. (1903). On the fatal effects of chloroform on children suffering from a peculiar condition of fatty liver. Lancet, 2, 10. Hill, 1. G. W. (1932a). The human heart in anaesthesia; an electrocardiographic study. Edinburgh Med. J., 39, 533.. - - (1932b). Cardiac irregularities during chloroform anaesthesia. Lancet, 1, 1139. Johnstone, M. (1952). Respiratory and cardiac control during endotracheal intubation. Br. J. Anaesth., 24, 36. Kirk, R. (1893). Death from chloroform. Br. Med. J., 1, 820. Levy, A. G. (1911). Sudden death under light chloroform anaesthesia. J. Physiol. (Land.), 42, 3P. - - (1912a). Ventricular fibrillation caused by stimulation of the cardiac accelerator nerves under chloroform. J. Physiol. (Lond.),44, 17P. - - (1912b). Sudden death under light chloroform anaesthesia. J. Physiol. (Land.), 43, 19P. - - (1922). ChloroformAnaesthesia, p~ 36. London: John Beale, Sons and Danielson. Morris, L. E. (1951). In Chloroform: a study after 100 Years (ed. R. M. Waters), p. 103. Madison: University of Wisconsin Press. . Nosworthy, M. D. (1937). The Theory and Practice of Anaesthesia. London: Hutchinson. Payne, J. P., and Conway, C. M. (1963). Cardiovascular, respiratory and metabolic changes during chloroform anaesthesia. Br. J. Anaesth., 35, 588. - - Senfield, R. M. (1964). Pronethalol in treatment of ventricular arrhythmias during anaesthesia. Br. Med. J., 1, 603. _ Poobalasingham, N., and Payne, J. P. (1978). The uptake and elimination of chloroform in man. Br. J. Anaesth., 50, 325. Smith, A. A., Volpitto, P. P., Gramling, Z. W., DeVore, M. B., and Glassman, A. B. (1973). Chloroform, halothane, and regional anaesthesia: a comparative study. Anesth. Analg. (Cleve.), 52, 1. Stiles, H. J., and McDonald, S. (1904). Delayed chloroform poisoning. Scott. Med. Surg, J., 15,97. Thomas, K. B. (1974). Chloroform: commissions and omissions. Proc. R. Soc. Med., 67, 723. - - (1975). The Development of Anaesthetic Apparatus. London: Blackwell Scientific Publications. Waters, R. M. (1951). Chloroform: A Study after 100 Years. Madison: University of Wisconsin Press.
J.
Anaesth. (1981), 53, lIS
CHLOROFORM IN CLINICAL ANAESTHESIA J. P.
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 attempting 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 particular 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 anaesthesia, 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 coinJ. 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 the inhaled concentration reached 8-10% chloroLincoln's Inn Fields, London WC2A 3PN; and The Anaesthetics Unit, The London Hospital Medical College, form. On this basis he set about designing an appropriate vaporizer to deliver known concenTurner Street, London El 2AD.
Chloroform probably has aroused more controversy 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 anaesthesia 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 immediate 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 popularity, 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-
0007--{)912/81/130011-o5 $01.00
'© 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 investigated thoroughly at such an early stage. The principal method for the preparation of anaesthetic chloroform involves the, chlorination of acetone or acetaldehyde by calcium hypochlorite 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 characteristics 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 evaporated. 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 introduced, 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, SurgeonMajor 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 controversy 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 breathed chloroform 0.5% in air, stimulation of the right cardio-accelerator nerve led to ventricular fibrillation and cardiac arrest, but that risk was substantially diminished when the inspired chloroform 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 accumulated 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 ventricular extrasystoles were not dangerous in themselves, but their importance lay in the ease with which they could lead to ventricular fibrillation.
CHLOROFORM IN CLINICAL ANAESTHESIA
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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 tristimuli 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 concentto 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 premediaction 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 anaesExcessive 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. During chloroform anaesthesia, spontaneous Fortunately, this combination of effects responds breathing is usual either through a Magill attachto atropine. 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 anaesinterpretation 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 conactivity 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 deThe 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 than that of 17.9 mg dl " 1 with a range of depress cardiac action. 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 supplemented by tubocurarine and assisted ventilation 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 reported by Poobalasingham and Payne for their series of patients whose lungs were ventilated using chloroform 1% after neuromuscular blockade 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 breathing. 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 equilibrium between the alveolar and pulmonary blood has become virtually constant after 1 h of chloroform 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 explanation ·lies in the fact that, in spontaneously breathing patients, the increase in the concentration of chloroform in the blood depresses breathing sufficiently to decrease the alveolar
BRITISH JOURNAL OF ANAESTHESIA ventilation. Consequently, the amount of chloroform 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 perfused adequately. The practical significance is that during controlled ventilation the chloroform concentration required is unlikely to exceed 1% whereas when patients are breathing spontaneously, 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 anaesthetists 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 chloroform 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 protection 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 suggested 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 results 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 inhalation agent which is also cheap, potent, nonexplosive 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. REFERENCES
Bevan, A. D., and Favill, H. B. (1905). Acid intoxication and late poisonous effects of anesthetics-hepatic toxemia, acute fatty degeneration of the liver following chloroform and ether anesthesia. J.A.M.A., 45, 691. Bourne, W. (196). Anesthetics and liver function. Am. J. Surg., 34,486. Geddes, 1. C. (1970). Metabolism of volatile anaesthetics; in Pharmacology Topics in Anaesthesia (International Anaesthesiology Clinics) (ed. R. Miller), p. 145. Boston: Little, Brown & Co.
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Gillies, J. (1948). Analyses of replies to a questionary on the use of chloroform at the present time. Anaesthesia, 3, 45. Goldschmidt, S., Ravdin, 1. S., and Lucke, B. (1935). The effect of oxygen in the prevention of the liver necrosis produced by volatile anesthetics. Am.J. Med. Sci., 189, 155. Guthrie, L. G. (1903). On the fatal effects of chloroform on children suffering from a peculiar condition of fatty liver. Lancet, 2, 10. Hill, 1. G. W. (1932a). The human heart in anaesthesia; an electrocardiographic study. Edinburgh Med. J., 39, 533.. - - (1932b). Cardiac irregularities during chloroform anaesthesia. Lancet, 1, 1139. Johnstone, M. (1952). Respiratory and cardiac control during endotracheal intubation. Br. J. Anaesth., 24, 36. Kirk, R. (1893). Death from chloroform. Br. Med. J., 1, 820. Levy, A. G. (1911). Sudden death under light chloroform anaesthesia. J. Physiol. (Land.), 42, 3P. - - (1912a). Ventricular fibrillation caused by stimulation of the cardiac accelerator nerves under chloroform. J. Physiol. (Lond.),44, 17P. - - (1912b). Sudden death under light chloroform anaesthesia. J. Physiol. (Land.), 43, 19P. - - (1922). ChloroformAnaesthesia, p~ 36. London: John Beale, Sons and Danielson. Morris, L. E. (1951). In Chloroform: a study after 100 Years (ed. R. M. Waters), p. 103. Madison: University of Wisconsin Press. . Nosworthy, M. D. (1937). The Theory and Practice of Anaesthesia. London: Hutchinson. Payne, J. P., and Conway, C. M. (1963). Cardiovascular, respiratory and metabolic changes during chloroform anaesthesia. Br. J. Anaesth., 35, 588. - - Senfield, R. M. (1964). Pronethalol in treatment of ventricular arrhythmias during anaesthesia. Br. Med. J., 1, 603. _ Poobalasingham, N., and Payne, J. P. (1978). The uptake and elimination of chloroform in man. Br. J. Anaesth., 50, 325. Smith, A. A., Volpitto, P. P., Gramling, Z. W., DeVore, M. B., and Glassman, A. B. (1973). Chloroform, halothane, and regional anaesthesia: a comparative study. Anesth. Analg. (Cleve.), 52, 1. Stiles, H. J., and McDonald, S. (1904). Delayed chloroform poisoning. Scott. Med. Surg, J., 15,97. Thomas, K. B. (1974). Chloroform: commissions and omissions. Proc. R. Soc. Med., 67, 723. - - (1975). The Development of Anaesthetic Apparatus. London: Blackwell Scientific Publications. Waters, R. M. (1951). Chloroform: A Study after 100 Years. Madison: University of Wisconsin Press.