Davison, Wynn and Dykes55 stated that chloroform was unlikely to produce ..... 1418â1420. 45. Sykes WS. Edward Laine and the Hyderabad Commission.
British Journal of Anaesthesia 1997; 79: 402–409
COMMENTARY
Clinical evidence for delayed chloroform poisoning
C. M. THORPE AND A. A. SPENCE
Summary
Case reports
From its introduction in 1847, chloroform proved to be a potent anaesthetic agent and over the next 50 yr its use became widespread. However, in 1912 the Committee on Anaesthesia of the American Medical Association stated that they were concerned with the occurrence of delayed chloroform poisoning in a number of cases. This conclusion was based on case reports and experimental animal data. However, subsequent studies and reported series of chloroform anaesthesia in humans have suggested a lower incidence of clinically significant liver injury. In this article we have investigated this discrepancy by analysing the published clinical data relating chloroform anaesthesia to liver damage. (Br. J. Anaesth. 1997; 79: 402–409).
Sheehan published his experience of anaesthesia with chloroform in labouring women.3 He noted that DCP occurred in patients with severe metabolic derangement after labours of 2–4 days or even longer, and he described the clinical course of illness: day 1: the patient is relatively well; day 2: vomiting occurs, with slight jaundice; day 3: the patient becomes seriously ill with restlessness, delirium, vomiting, upper abdominal pain, increasing jaundice and a low pyrexia; day 4: comatose with “characteristic groaning”; and day 5: deepening coma, increase in temperature and death. Post-mortem histology showed mid-zonal or centrilobular necrosis of the liver. However, not all patients would develop the full syndrome and die. Davison’s description of the clinical illness4 concurred with Sheehan’s account. In many of the case reports before 1912 it can be seen that the course of illness did not fit that of hepatic damage (table 1). Therein lies one of the major problems of that time: DCP did not have a defined aetiology and clinical pattern. Because of this, a wide variety of causes of death after anaesthesia were attributed to a late poisonous effect of chloroform. Reading the case reports in table 1 it can be seen, for example, that Heyfelders’ two cases5 are convincing histories of liver failure, whereas others such as Guthrie’s publications9 11 indicate other diagnoses. Bevan and Favill restricted the array of postoperative deaths attributed to chloroform by defining the underlying role of the liver in 1905.15 They described late chloroform poisoning as a “hepatic toxaemia” causing vomiting, restlessness, fright, mild delirium, convulsions, coma, Cheyne–Stokes breathing, cyanosis and icterus in varying degree. They wrote that death usually ensued, and that fatty degeneration of the liver was seen post mortem. After their review, the term “delayed chloroform poisoning” (DCP) started to appear widely in the literature and the 1912 committee on anaesthesia equated DCP with necrosis of the liver.
Key words Anaesthetics volatile, History, chloroform.
chloroform.
History,
anaesthesia.
James Young Simpson discovered the anaesthetic properties of chloroform in 18471 and introduced it into clinical practice in Edinburgh. He enthusiastically proclaimed it to be a superior drug to ether. Chloroform proved to be a potent anaesthetic agent and over the next 50 yr its use became widespread throughout the world. However, in 1912 the Committee on Anaesthesia of the American Medical Association pronounced that “The use of chloroform as the anaesthetic for major surgery is no longer justifiable”.2 They were concerned that “delayed chloroform poisoning occurred in a by no means inconsiderable number of cases”. At this time, there were no accurate records of the incidence of delayed chloroform poisoning (DCP) and their conclusion was based on case reports backed by experimental animal data. However, subsequent studies and reported series of chloroform anaesthesia in humans have suggested a lower incidence of clinically significant liver injury. We were interested to explore this discrepancy by analysing the published clinical data relating chloroform anaesthesia to liver damage. Information may be divided into three groups: case reports of DCP, large series of chloroform administration and comparative studies.
C. M. THORPE*, MBBS, FRCA, A. A. SPENCE, CBE, MD, FRCA, FRCPED, FRCS, University Department of Anaesthesia, University of Edinburgh, Edinburgh Royal Infirmary, Lauriston Place, Edinburgh EH3 9YW. Accepted for publication: May 12, 1997. *Address for correspondence: Anaesthetic Department, Gwynedd Hospital, Bangor, Gwynedd LLS7 2PW.
Clinical evidence for delayed chloroform poisoning We found 74 cases in the literature dating from before 1912. The evidence for death secondary to liver failure was very variable in these reports, with jaundice documented in only 20 cases. Frequently the finding of a fatty liver at post mortem was thought to be a sign of death secondary to DCP. In all, only 18 cases stand up to scrutiny as being potential instances of death secondary to liver failure, whereas 35 cases have clinical histories which suggest other causes of death. Twenty-one reports do not have enough information to determine if chloroform could have had an influence on the clinical course. The case reports published after 1912 (table 2) have a higher proportion of patients with a clinical history compatible with liver failure. We found 49 case reports of patients with DCP in the literature, and 30 of these had documented jaundice. Eighteen patients had a history compatible with liver failure after chloroform anaesthesia, and only four patients had a history which suggested other pathology. In 27 of the 49 reports there was insufficient evidence to form a conclusion.
Large series (table 3) The three large series published before 1912 had no documented reports of DCP. Snow,42 Lawrie45 and Neve44 had records of 115 550 chloroform anaesthetics in total. Lawrie and Neve practised anaesthesia in India at the turn of the century. They stand out as having safe records of chloroform anaesthesia; however the nature of postoperative care at this time implied that follow-up of their patients was limited. Between 1948 and 1970 several articles documented the incidence of hepatic damage after chloroform. Eleven authors documented a total of 310 274 chloroform anaesthetics. There were three deaths from liver failure and another six deaths in which it is unclear if the liver was involved. This gives an incidence of fatalities from liver failure of between 1 in 34 474 and 1 in 103 424. Three more patients with severe hepatic damage recovered. The incidence of documented jaundice was 1 in 10 342.
Comparative studies (table 4) Nine studies comparing chloroform anaesthesia with control (usually halothane) did not show a clinically significant difference in liver damage. Orth57 found detectable jaundice in six patients compared with three in the control group. However, numbers in these studies were small.
Discussion Clearly the problem of liver damage after chloroform anaesthesia is not as great as was feared in 1912. A large number of case reports of DCP do not stand up to scrutiny. In many of these, the description is not that of hepatic failure and in those patients who have a reasonable history of liver damage it is difficult to implicate chloroform as the certain cause. However, it does seem reasonable to assume that there is at
403 least some degree of hepatotoxicity in humans. The mechanism by which this may occur has not been elucidated fully, but it is thought to occur via active metabolites after hepatic metabolism of chloroform.65 Hepatic chloroform degeneration proceeds by cytochrome p450-dependent oxidative pathways, producing reactive metabolites. These are prevented from covalently binding to microsomal proteins by hepatic glutathione (GSH). Phosgene, a reactive metabolite of chloroform, depletes hepatocellular glutathione.61 The hepatotoxicity of chloroform may therefore be related to two factors: the rate of biotransformation of chloroform into its active metabolites and the availability of GSH to mop up these metabolites. Enzyme induction increasing the rate of metabolism may occur in association with barbiturates, alcohol and severe starvation, and this may explain the possible increase in hepatic damage with chloroform in patients with these conditions. A direct effect of chloroform on the hepatic microsomal calcium pump has also been suggested.66 Other causes of liver damage were prominent in the days of chloroform anaesthesia. Hypoxia and hypercapnia cause liver damage, irrespective of the anaesthetic agent used58 and many anaesthetics were given in which the patient had a poor airway. The lack of supplementary oxygen compounded the problem and it is reasonable to assume that there were many hypoxic patients undergoing the knife. It is worth noting that the excellent safety records of Neve44 and Lawrie45 were achieved by anaesthetists who placed great importance on maintaining a clear airway. In addition, the hepatic effects of chloroform are thought to occur more frequently in those patients with predisposing factors, such as hypoxia, hypercapnia, dehydration and acidosis, and alcoholism. There is no doubt that in the early years of anaesthesia these events were more likely to occur. The possibility of predisposition to liver damage was explored by Ballin in 1903.12 He reviewed 10 cases of acute yellow atrophy of the liver, eight of which had been given chloroform. He made the point that in every case an inflammatory condition such as appendicitis was present and six of the cases were laparotomies. He thought that this predisposed the liver to the effects of chloroform, and also strongly inferred alcohol as a causative factor. More recently, others have formed the conclusion that chloroform has had a rough deal. Davison, Wynn and Dykes55 stated that chloroform was unlikely to produce damage to the liver when used in clinical doses for light anaesthesia. Dykes67 pointed out that early workers were not successful in proving the existence or determining the incidence of DCP in humans. Davison4 wrote that chloroform, administered by modern techniques, is no more dangerous than halothane. Strunin43 analysed the evidence and concluded that chloroform did not entirely fit the criteria required for a drug to be classified as a hepatotoxin. Modern criteria for diagnosing drug-induced hepatotoxicity require stringent investigation. Factors that need to be taken into consideration are the temporal relationship of the disease to starting
5
1902
1903
1903
Brewer10
Gutlhrie11
Ballin12
Dorner Foerster7
7
Steinthal7 Salen and Wallace7
1899 1902
1896 1899
1903 1904
1894
Guthrie9
Montgomery Stiles and McDonald7
1890
Bastinelli7 8
13
1862 1850
1847
Date
Casper6 7 Berend6 7
Heyfelder
Author
No details
Necrotic tissue and pus in the abdomen 2h 2h No details
3. Perityphilitis
Hernia 1. Osteotomy femurs
Fistula of caecum 1. Laparotomy for salpingo-oophritis 2. Appendicectomy No details 50 min
Jaundice, rapid pulse, coma Jaundice, weakness, rapid pulse
22 min. Uneventful
2. Genu valgum
Inguinal hernia 1. Inguinal hernia
Pyrexia, and “cardiac weakness” Cardiac weakness and vomiting (black vomit)
Restlessness, coma Restlessness, vomiting, pyrexia, jaundice, rapid pulse and coma Vomiting, restlessness, thirst, rapid pulse, cyanosis, coma, death No details
Vomiting, jaundice, restlessness, coma
None Chloroform taken well 20 min 10–15 min. Chloroform taken well 25 min. Chloroform tolerated well Uncomplicated 20 min
Crying, vomiting, restless, flushed, t:103F Delirium, paroxysms, respiration high, weak pulse, t:103C Vomiting, urine output low, coma Vomiting, jaundice, unconsciousness Vomiting, restlessness, rapid pulse Vomiting, pyrexia, shivering. Became blue
Collapsed, vomiting, restless, delirious, t:104.6F Shocked 12 h after operation, t:99.2F
Screaming, sweaty and cold, t:98F Screaming, vomiting and restless, t:103F Vomiting and delirium, t:102F Vomiting, t:101F Vomiting, delirium, restlessness, coma, t:98F Collapsed. Excessive vomiting, t:98.6F
Restlessness, vomiting. Jaundice in one case
Generalized spasms
Restless, fever, delirium Never recovered senses Vomiting, small volume, frequent pulse Venesected
Restless, stupor, delirium
Postoperative course
1. TB of knee 2. Webbed fingers 3. Shoulder naevus 4. Posterior pharyngeal abscess Appendix
9. Double psoas abscess Gangrenous appendix
8. Iliac abscess
Chloroform taken well. 15 min 1h 25 min
Took anaesthetic well. Long operation Chloroform taken badly
6. Hydrocele
7. Iliac abscess
No details No details 1h Vomited twice 70 min
Severe cardiovascular depression No details No details 45 min. Stopped three times because of inky coloured blood Cried repeatedly on being cut Not described except for the inky colour of blood No details
Intraoperative course
1. Vesical calculus 2. Aspiration of knee 3. Genu valgum 4. Tapiles equinovarus 5. Genu valgum
3 cases
2. Amputation 3–10
2. Amputation Amputation 1. Removal of shoulder blade
1. Amputation
Operation
Table 1 Case reports before 1912
British Journal of Anaesthesia 1997; 79: 402–409
No No
No details
Yes Yes
No
No
No Yes
Yes
No Yes No No
No No
No
No
No
No No No No No
Yes
No
Yes No No
Yes
Jaundice?
42 h 48 h
2 days
5 days 3 days
9 days
26 h
48 h 3 days
Recovered
3 days 4 days 28 h 33 h
16 h 4 days
14 h
6 days
24 h
10 h 12 h 27 h 30 h 53 h
3–10 days
No details
8 days 9 days 17 h
8 days
Death
Fatty degeneration of liver, heart, kidneys Fatty changes in internal organs Extreme fatty change
Yellow fatty liver. Pneumococcus in lung Fatty degeneration, worse centrally No details Fatty degeneration of the liver
Liver buff colour Yellow fatty liver
None
Fatty liver Fatty degeneration of the liver No details No PM
Fatty liver on section Not done
No apparent cause of death
No PM
Fatty infiltration
Fatty changes, mostly central in one case Normal liver Pus in kidneys Liver pale and grey Fatty infiltration of the liver Small liver
No details
No details No details Fatty liver
Nutmeg liver
Post mortem
404 British Journal of Anaesthesia
1895 1896
1896 1902
1895 1890
Stocker15 Bandier15
Marthen15 Cohn15
Erlagh15 16 Thiem and Fishcer7 15 Fraenkel15 17
1908 1908
1908
1908
1908 1909
1909 1909
1909
Thorp19 Telford20
Bride21
Wilson22
Taylor23 Somerville16
Weir24 Payne25
Whipple and Sperry26 Telford27
1910
1906
Telford and Falconer18
1892
Gangrenous ovarian cyst
1905
30 min
No details
Intraoperative course
25 min. Chloroform not taken well 15 min
2. inguinal hernia
No details
3. Appendicitis
35 min. Good anaesthesia and recovery No details
Uneventful No jaundice. All recovered
No details
2. Twisted ovarian cyst
Appendix 45 min 3 cases of protracted vomiting. Incision and drainage chest wall abscesses Pyloric stenosis
20 min. Uneventful ACE mixture
15 min 90 min
2. Genu valgum Tuberculous hip
Inguinal hernia 1. Genu valgum
20 min
25 min 15 min. Straightforward
2. Genu valgum 3. Inguinal hernia
1. Tapiles
Well taken, 7 min 20 min
Circumcision 1. Tuberculous
3. Osteotomies femur and tibia
No details
1. Cleft palate
Prolonged induction and plenty of chloroform Strangulated ovarian cyst No details Incarcerated inguinal Anaesthesia easily produced hernia Dental extraction 40 min Removal of uterine Took chloroform well adnexae Extirpation of uterus Bilroths mixture Removal of blood from No details knee joint 5 cases 2–4 h
Osteotomy of the elbow
2. Appendix
Operation
1905
Date
Carmichael and Beattie14 Bevan and Favill15
Foerster
Author
Table 1 Case reports before 1912—continued
British Journal of Anaesthesia 1997; 79: 402–409
Vomiting, delirium, restlessness, jaundice, rapid pulse and respiration Vomiting, restlessness, coma
Vomiting coffee grounds, abdominal pain Nausea, thirst, apathy, restlessness haematemesis Restlessness, vomiting, rapid pulse, coma Vomiting, fast pulse and respiration, coma, slight yellowing of skin, t:106F Vomiting, decreased urine output, rapid pulse, jaundice Vomiting coffee grounds, jaundice, rapid pulse, collapse, t:102F Restlessness, delirium, coma
Vomiting, increasing drowsiness, coma, t:102F Collapse 1st day after operation. Vomiting coffee grounds. Became white and cold Rapid pulse, restlessness, decreased mental state. Briefly responded to 30 oz saline, then coma and death Vomiting, rapid pulse, noisy respiration coma Vomiting, restlessness, rapid pulse and respiration. No urine output Restlessness, vomiting, rapid pulse Vomiting coffee grounds. Melaena. Yellow tinge to skin Vomiting coffee grounds, rapid pulse, coma
No details
Delirium, increasing pulse rate and temperature. Convulsions Restlessness, ictenus, coma, death Delirium, jaundice, petechiae, haemorrhage, coma, t:40C Vomiting, restlessness, jaundice Restless, vomiting, delirium, coma, jaundice. Pulse 150 Icterus, delirium No details
Restlessness, vomiting, jaundice, pyrexia, rapid pulse, coma Restlessness, thirst, vomiting, coma
Postoperative course
No
Yes
No
Yes
Yes
No Yes
No Yes
No
No Yes
No No
No
No
No
No details
Yes No details
Yes Yes
Yes Yes
No
No
Yes
Jaundice?
4 days
3 days
Recovered
89 h
60 h
38 h 20 h
Recovered 8 days
32 h
2 days Recovered
37 h 40 h
60 h
1st day
57 h
40 h–20 days
No details 4 days
3 days 4 days
No details 4 days
110 h
42 h
5 days
Death
Extreme central necrosis of the liver Yellow liver, extreme fatty degeneration
Central necrosis peripheral fat
Central necrosis peripheral fat
Yellow liver with fatty infiltration Extremely fatty liver Not done
Pale yellow liver. Intense fatty change
Not done Yellow liver. Extreme fatty change Extreme fatty change
Fatty degeneration of the liver
Fatty changes in the liver in 4 cases Liver canary yellow with fatty degeneration Fatty degeneration in all organs
Acute yellow atrophy Fatty degeneration of the liver
Fatty degeneration of the liver Icteric nutmeg liver
Enlarged yellow liver. Intense fatty change Peritonitis. Fatty liver especially peripherally Acute yellow atrophy Acute yellow atrophy
Yellow liver with fatty changes
Post mortem
Clinical evidence for delayed chloroform poisoning 405
Date
1914 1924
1925
1928 1931
1932
1934
1935
1936
1939
1939
1940
1942
1962
Author
Fairlie28
Stander29
Royston30
Gilliat31
Willcox32
Stander33
Todd34
Gibberd35
Grant and Miller36
Townsend37
Sheehan38
Sheehan39
Crawford40
Marx and colleagues41
2.2 cases termination for hyperemesis 5 obstetric cases. All dehydrated and acidotic Laminectomy
1. Forceps, 68 h labour 2. Second stage labour 1. 4 patients with either hyperemesis or vomiting of late pregnancy 2. 8 patients also quoted from other sources. Presumed to have had chloroform, however only documented in 2 1. 7 obstetric cases
5.5 h. Severe blood loss and transfusion at one point
No details
No details
No details
No details No details
1h Two anaesthetics “a long time” 30 min No details Light chloroform
2. Forceps (30 h labour) 3. Forceps
1. Manual rotation 2. Forceps 3. Labour
35 min
No details
30 min
1. Forceps (48 h labour)
Second stage and repair of tear (2 day labour) Induction for disproportion
3 vomiting, jaundice, restlessness, delirium, 2 milder-just jaundice “In distress” followed by sudden stiffening and apnoea
No details
Jaundice from day 2
No details
Headache, fever, jaundice, coma, rapid pulse Vomiting, jaundice. Resolved after 7 days Developed scarlet fever after operation. Transient jaundice on day 5 jaundice, vomiting, coma Vomiting, jaundice, coma, dilating pupils Died from either “clinical picture of DCP” and sepsis or from cerebral symptoms
Vomiting, drowsiness, rapid pulse coma? slight icterus after death Vomiting, jaundice, restlessness, coma rapid pulse, t:103F, convulsions Jaundice, coma. Pulse 150, t:102F Drowsy, jaundice, coma, t:102.4F
Increasing drowsiness and convulsion
“Abdomen much distended post delivery” Placental bleeding, vomiting, jaundice, coma “5 cases of delayed chloroform poisoning” Restlessness, jaundice, coma Drowsy, vomiting, jaundice, coma
No details No details No details No details
Jaundice, impaired consciousness, coma
No details
2. Craniotomy for fetal hydrocephalus (16 h labour) 3. EUA and delivery (24 h labour)
No details 1. Forceps 2. Appendix
Jaundice? Not done No details
Post mortem
Central necrosis and fatty degeneration Central necrosis and peripheral fatty infiltration Central necrosis fat peripherally Diffuse necrosis and peripheral fat
No details Central necrosis peripheral fat Degeneration of liver cells and fatty degeneration Central necrosis of liver
No details
7 days Acute yellow atrophy Recovered Recovered
5 days 6 days
8 days
100 h
3 days
No details 4 days 5 days
3 days
Centrilobular and mid-zone necrosis Recovered None
3 days
77 h 3 days
Death
No
Yes
No details
Yes
4 mid-zonal tending to centrilobular necrosis, 2 midzonal and centrilobular necrosis, 1 mid-zonal necrosis Centrilobular necrosis
2 days
Yellowish liver. Mild centrilobular necrosis
Recovered None
3–4 days
3–5 days
Yes 2 days Liver necrosis Yes Recovered None Yes No details 2 gross centrilobular necrosis, 1 (presumed) centrilobular fat, 1 fat throughout lobule No details No details Centrilobular necrosis
Yes Yes Yes
Yes Yes
Yes
No
No
No details Yes Yes
Yes
Yes
Vomiting, dullness, coma No Drowsy, restlessness, vomiting, jaundice rapid pulse, cyanosis, Yes t:102F Jaundice, abdominal pain, vomiting Yes
Postoperative course
No details
38 min. Protracted induction 69 min
Intraoperative course
1. Forceps. 108 h labour
Laparotomy Forceps
Operation
Table 2 Case reports after 1912
British Journal of Anaesthesia 1997; 79: 402–409
406 British Journal of Anaesthesia
Clinical evidence for delayed chloroform poisoning
407
Table 3 Large series of chloroform anaesthesia Author
Date
Number
Incidents
42
1858
4000
Neve44
1898
Lawrie45 Middleton46
1901 1948
1.15 843 2. 78 407 17 300 1. 3000
Gillespie47
1950
2. 4500 1111
Lenahan and Babbage48 Potter48 Buerger and colleagues49
1950
Duncan and colleagues50
1956
9724 2500 1. 20 000 2. 129 530 3. 60 000 18 302
63 postoperative deaths. No documented jaundice or liver damage 2 deaths ?intraoperative. No mention of jaundice or DCP 3 deaths, no details No mention of jaundice or DCP As a Japanese prisoner of war. 1 patient with coma and death after 48 h No fatalities secondary to the anaesthetic 10 patients with deranged liver function 1 patient died from bronchopneumonia No maternal deaths associated with anaesthesia 2 deaths. No details 2 patients with toxic hepatitis 1 death from delayed chloroform poisoning 4 deaths but not specified whether liver involved 1 death from fulminating pre-eclampsia. No jaundice
1960
154
Snow
Dobkin and colleagues
51
1955
1960
Siebecker and colleagues52 Fote53
1960
Whitaker and Jones54 Davison55
1965 1970
Post mortem No details No details No details Acute yellow atrophy Recovered Fatty degeneration Recovered No details No details Peripheral necrosis in the liver
5 patients with pre-existing jaundice. 4 patients developed jaundice: a) 3 h gastrectomy. Developed jaundice and had tarry stool Recovered b) Cholecystectomy. Previous jaundice. Subphrenic abscess Recovered and mild jaundice c) Gastrectomy, Roux en Y. Bronchopneumonia and Metastatic cancer jaundice Fatty degeneration of the liver d) Total colectomy. Transfused. Transient jaundice Recovered 1210 1 death from hepatic damage. Patient had 20–30 m No details of inadequate ventilation intraoperatively. 1. 9669 Obstetric Asymptomatic jaundice in 8 patients 1 patient with jaundice, lethargy, hypoglycaemia, convulsion and coma Recovered 1 patient with severe pre-eclampsia, pyelonephritis, septicaemia, jaundice and uremia No details 2. 199 Obstetric 1 patient developed jaundice 1502 1 patient with transient jaundice.? infectious hepatitis 1. 1373 Follow-up limited but no suspicion of jaundice 2. 25 307 No liver damage
Table 4 Comparative studies of chloroform anaesthesia Author Beesly
56
Orth57 Sims and colleagues
58
Bamforth and colleagues59 60
Year
Study (patient numbers)
Results
1906
Chloroform (19) vs ether (24) vs mixture (3). All with appendicitis.
1950
Chloroform (65) vs other (56)
1951
Chloroform (38) vs ether (40)
1960
Chloroform vs halothane (? 100 patients in total) Chloroform (29) vs halothane (32) Chloroform (315) vs halothane (548)
14 deaths with chloroform, 2 with “delayed poisoning”. No jaundice. 2 deaths with ether. 1 death with the mixture of the two. Detectable jaundice in 6 chloroform patients and 3 “other” patients. No difference in hepatic injury between anaesthetic agents. No liver injury in either group
Jones McReynolds and colleagues61
1963 1963
Griffiths and Ozguc62 Oduntan63 Smith and colleagues64
1964 1968 1973
Chloroform (30) vs halothane (27) Chloroform (50) vs halothane (50) Chloroform (58) vs halothane (42) vs regional anaesthesia (12)
and stopping the drug, clinical pattern of the illness, epidemiological evidence, exclusion of other causes, assessment for pre-existing liver disease and the result of liver biopsies. Another investigation into causality, the re-challenge test, is too dangerous for routine use. These criteria were obviously not followed during the tarring of chloroform. Many other volatile agents have been implicated in liver damage. Their postulated idiosyncratic role in severe liver damage differs from the direct action proposed for chloroform and
No complications with either group No difference between groups. 1 patient with chronic liver disease died after 2 anaesthetics—one with each anaesthetic agent! No difference in liver enzyme changes No problems with either group No significant difference in liver function tests except BSP retention higher with chloroform
is discussed in detail by Ray and Drummond68 and Elliot and Strunin.69 Modern anaesthesia provides accurate delivery of anaesthetic agents, and diligently monitors the airway and cardiovascular status. Given these accepted prerequisites for safe anaesthesia, chloroform does not have a high incidence of clinically significant hepatic damage. The incidence of hepatic failure after chloroform is between 1 in 25 800 and 1 in 51 700 and compares favourably with halothane, which is quoted as 1 in 35 000.69
408
References 1. Simpson JY. On a new anaesthetic agent, more efficient than sulphuric ether. Lancet 1847; 2: 549–550. 2. Report of the Committee on Anaesthesia. Journal of the American Medical Association 1912; 58: 1908–1910. 3. Sheehan HL. Delayed chloroform poisoning. British Journal of Anaesthesia 1950; 22: 204–217. 4. Davison MHA. Chloroform. British Journal of Anaesthesia 1965; 37: 655–660. 5. Defalque RJ. The first delayed chloroform poisoning. Anesthesia and Analgesia 1968; 47: 374–375. 6. Casper JL. The Handbook of Practice of Forensic Medicine, 2nd Edn. London: New Sydenham Society, 1862. 7. Stiles HJ, McDonald S. Delayed chloroform poisoning. Scottish Medical and Surgical Journal 1904; 15: 97–149. 8. Bastianelli R. Abstract. Revue des Sciences Medicales en France et a l’Etranger 1892; 39: 625. 9. Guthrie LG. On some fatal after effects of chloroform on children. Lancet 1894; 1: 193–197. 10. Brewer GE. Fatal acetonemia following an operation for acute appendicitis. Annals of Surgery 1902; 36: 481–493. 11. Guthrie LG. On the fatal effects of chloroform on children suffering from a peculiar condition of fatty liver. Lancet 1903; 2: 10–17. 12. Ballin M. Acute yellow atrophy of the liver as a sequela to appendectomy. Annals of Surgery 1903; 37: 362–371. 13. Montgomery WP. The fatal effects of chloroform on children suffering from a peculiar condition of fatty liver. Lancet 1903; 2: 267. 14. Carmichael EW, Beattie JM, Delayed chloroform poisoning. Lancet 1905; 2: 437–440. 15. Bevan AD, Favill HB. Acid intoxication and late poisonous effects of anesthetics. Journal of the American Medical Association 1905; 45: 691–696, 754–759. 16. Somerville TC. Three cases of delayed chloroform poisoning. Lancet 1909; 2: 81–82. 17. Bourne W. Anaesthetics and liver function. American Journal of Surgery 1936; 34: 486–495. 18. Telford ED, Falconer JL. Delayed chloroform poisoning. A clinical study with a report of three fatal cases. Lancet 1906; 2: 437–440. 19. Thorp H. A case of acid intoxication following the administration of chloroform. Lancet 1908; 1: 623. 20. Telford ED. Three cases of a delayed chloroform poisoning. Lancet 1908; 1: 623–624. 21. Bride TM. A report on two cases of delayed chloroform toxaemia. Lancet 1908; 1: 625–626. 22. Wilson HC. A fatal case of delayed chloroform poisoning. Lancet 1908; 1: 626–627. 23. Taylor MF. Fatal toxaemia after administration of chloroform. Lancet 1908; 2: 799–800. 24. Weir AA. A case of “delayed chloroform poisoning” treated with dextrose; recovery. Lancet 1909; 2: 710. 25. Payne WH. Delayed chloroform poisoning. Lancet 1909; 2: 187. 26. Whipple GH, Sperry JA. Chloroform poisoning liver necrosis and repair. Bulletin of the Johns Hopkins Hospital 1909; 20: 278–289. 27. Telford ED. Some notes on delayed chloroform poisoning. Lancet 1910; 2: 1269–1270. 28. Fairlie HP. A case of delayed chloroform poisoning. Lancet 1914; 2: 1411–1412. 29. Stander HJ. A chemical study of a case of chloroform poisoning. Bulletin of the Johns Hopkins Hospital 1924; 35: 46–49. 30. Royston GD. Delayed chloroform poisoning following delivery. American Journal of Obstetrics and Gynecology 1925; 10: 808–814. 31. Gilliat W. Discussion on anaesthetics in obstetrics. Proceedings of the Royal Society of Medicine 1927; 28: 11–1136. 32. Willcox W. Toxic jaundice. Lancet 1931; 2: 1, 51, 111. 33. Stander HJ. Delayed chloroform poisoning. American Journal of Obstetrics and Gynecology 1932; 23: 882–885. 34. Todd TF. Delayed chloroform poisoning. Lancet 1934; 2: 597–598. 35. Gibberd GF. Delayed chloroform poisoning in obstetric practice. Guys Hospital Report 1935; 85: 142–160. 36. Grant J, Miller JH. Puerperial jaundice. Glasgow Medical Journal 1936; 125: 165–171.
British Journal of Anaesthesia 37. Townsend E. Acute yellow atrophy of the liver. British Medical Journal 1939; 2: 558–560. 38. Shehan HL. The pathology of hyperemesis and vomiting of late pregnancy. Journal of Obstetrics and Gynaecology of the British Empire 1939; 46: 685–699. 39. Shehan HL. The pathology of acute yellow atrophy and delayed chloroform poisoning. Journal of Obstetrics and Gynaecology of the British Empire 1940; 47: 49–62. 40. Crawford MD. Clinical and biochemical findings in delayed chloroform poisoning. Journal of Obstetrics and Gynaecology 1942; 49: 549–555. 41. Marx GF, Kikkaura Y, Orkin LR. Delayed chloroform poisoning. Report of a case. Anesthesia and Analgesia 1962; 41: 575–581. 42. Snow J, Ellis RH, eds. The Casebooks of Dr John Snow. London: Wellcome Institute for the History of Medicine, 1994. 43. Strunin L. The Liver and Anaesthesia. London: WB Saunders, 1977. 44. Neve A. Chloroform in India. British Medical Journal 1898; 2: 1418–1420. 45. Sykes WS. Edward Laine and the Hyderabad Commission. In: Sykes WS, eds. Essays on the First 100 Years of Anaesthesia, vol. 3. Edinburgh: Churchill Livingston, 1982; 199–232. 46. Middleton DS. Experiences with chloroform as an anaesthetic agent. Anaesthesia 1948; 3: 53–57. 47. Gillespie NA. A clinical evaluation of chloroform. In: Waters RM, eds. Chloroform. A Study After 100 Years. Winsconsin: University of Wisconsin Press, 1951. 48. Lenahan RM, Babbage ED. A review of chloroform anaesthesia in obstetrics. New York State Journal of Medicine 1950; 50: 1717–1720. 49. Buerger PT, Sanderson GM, Rekate AC. An experimental and clinical re-evaluation of chloroform anaesthesia in obstetrics. Surgical Forum 1955; 6: 465–468. 50. Duncan C, Hindman JFD, Mayberger HW. Chloroform as an obstetrical anesthetic. American Journal of Obstetrics and Gynecology 1956; 72: 1004–1006. 51. Dobkin AB, Skinner LC, Johnston HJ. A study of chloroform anaesthesia in a precision system. Canadian Anaesthetists Society Journal 1960; 6: 379–398. 52. Siebecker KL, Bauforth BJ, Steinhaus JE, Orth OS. Clinical studies on new and old hydrocarbons. Anesthesia and Analgesia 1960; 39: 180–188. 53. Fote FA. Hepatic effects of chloroform anesthesia in obstetrics. American Journal of Obstetrics and Gynecology 1960; 79: 1142–1147. 54. Whitaker AM, Jones CS. Report of 1500 chloroform anesthetics administered with a precision vaporiser. Anesthesia and Analgesia 1965; 44: 60–65. 55. Davison MHA, Wynne NA. Chloroform since 1920. In: Dykes MHM, eds. Anaesthesia and the Liver, 8th Edn. Boston: Little Brown, 1970. 56. Beesly L. Post anaesthetic acetonuria. British Medical Journal 1906; 1: 1142–1148. 57. Orth OS, Pohle FS, Sims L. The effect of chloroform on hepatic function. In: Waters RM, eds. Chloroform. A Study After 100 Years. Wisconsin: University of Wisconsin Press, 1951. 58. Sims JL, Morris LE, Orth OS, Waters RM. The influence of O2 and CO2 levels during anaesthesia on postsurgical hepatic damage. Journal of Experimental and Clinical Medicine 1951; 38: 388–396. 59. Bamforth BJ, Siebecker RL, Steinhaus JE, Orth OS. A clinical comparison of chloroform and halothane by a blind study technique. Anesthesia and Analgesia 1960; 2: 273–280. 60. Jones CS. A clinical comparison of halothane and chloroform anesthesia. Anesthesia and Analgesia 1963; 42: 348–354. 61. McReynolds EL, Thorogood A, Morris EL. Clinical comparison of halothane and chloroform. Archives of Surgery 1963; 36: 633–640. 62. Griffiths HWC, Ozgvc L. Effects of chloroform and halothane. British Journal of Anaesthesia 1964; 37: 246–247. 63. Oduntan SA. Chloroform anaesthesia. A clinical comparison of chloroform and halothane administered from precision vapourizers. Anaesthesia 1968; 23: 552–557. 64. Smith AS, Volpitto PP, Gramling ZW, Devure MB, Classman AB. Chloroform, halothane and regional anesthesia. A comparative study. Anesthesia and Analgesia 1973; 52: 1–11.
Clinical evidence for delayed chloroform poisoning 65. Brown BR, Sipes IG, Saglyn AM. Mechanisms of acute hepatic toxicity: Chloroform, halothane, and glutathione. Anesthesiology 1974; 41: 554–561. 66. Moore L. Inhibition of liver microsome calcium pump by in vivo administration of CCL4, CCL3 and 1,1-dichloroethylene (vinyldene chloride). Biochemical Pharmacology 1980; 29: 2505–2511.
409 67. Dykes MHM. The early years: 1846–1912. In: Dykes MHM, eds. Anaesthesia and the Liver. Boston: Little Brown, 1970. 68. Ray DC, Drummond GB. Halothane hepatitis. British Journal of Anaesthesia 1991; 67: 84–99. 69. Elliot RH, Strunin L. Hepatotoxicity of volatile agents. British Journal of Anaesthesia 1993; 70: 339–348.
