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Fulminant hepatic failure following halothane anaesthesia
J O U R N A L
O F
CLINICAL FORENSIC MEDICINE Journal of Clinical Forensic Medicine 12 (2005) 271–273 www.elsevier.com/locate/jcfm
Case report
Fulminant hepatic failure following halothane anaesthesia G. Pradeep Kumar a, Vrinda J. Bhat a
a,* ,
Vasantha Sowdi
b
Department of Forensic Medicine, Kasturba Medical College, Manipal 576104, India b Department of Pathology, KSHEMA, Mangalore, India Available online 8 August 2005
Abstract The forensic pathologist is responsible for determining the cause, manner and approximate time of death and injury. After recording the detailed description of the external and internal appearances, a short summary should be offered of the major positive findings and their relationship to the cause of death. In many cases this will be obvious, however when the findings are less clear-cut, or are multiple, then the alternatives should be discussed detailing the possible sequence of events and interpreting the findings in concluding the cause of death. It is essential to causally connect the autopsy findings to the cause of death. We present a case report wherein a person who sustained avulsion injury to his left hand in an industrial accident, died due to, fulminant hepatitis, hepatic encephalopathy and acute renal failure, having undergone six operations under general anesthesia with halothane during his stay in the hospital. 2004 Published by Elsevier Ltd and AFP. Keywords: Hepatic failure; Halothane toxicity; Hepatic encephalopathy
1. Introduction Risk factors for hepatotoxicity includes repeated exposure to halothane, prior history of jaundice, fever after halothane, obesity, middle-aged females and intra operative hypotension. Pre-existing liver disease probably does not increase susceptibility.1 Weber reported an unusual case of halothane induced hepatic failure in a 22 years old, wherein the typical risk factors of age over 40, female, obesity and previous exposure to halothane were not present.2 Hepatitis has also been described in three individuals who sniffed halothane repeatedly in order to obtain a drug high.3 Halothane hepatitis is much more frequent after multiple anesthetics. Jaundice appears about 10–28 days after a single exposure and 3–17 days after multiple exposures. This delay before jaundice is helpful in excluding *
Corresponding author. Tel.: +9844426463 (Mobile); fax: +91 820 2570061/2570062 E-mail address: [email protected] (V.J. Bhat). 1353-1131/$ - see front matter 2004 Published by Elsevier Ltd and AFP. doi:10.1016/j.jcfm.2004.10.019
other causes of postoperative icterus. If the patient becomes icteric, the mortality is very high.4 Fatal cases are characterized by progressively deepening jaundice, hemorrhagic phenomenon, ascites and coma. Prothrombin time is one of the best prognostic indicators; a prothrombin time of more than 20 s indicates a high likelihood of a fatal outcome.3 The hepatic injury is cytotoxic comprising of centrizonal necrosis or massive necrosis and minimal fatty changes. Inflammatory infiltration is much less prominent in halothane-induced injury than in viral hepatitis.5
2. Case report A 38-year-old male was admitted to Kasturba Medical College Hospital, Manipal for the treatment of an avulsion injury sustained on his left upper limb measuring 39 · 8 cm along with fractures of left humerus, radius and ulna. He was subjected to multiple (six) surgical procedures under general anesthesia using halothane over a period of 18 days for wound debridement,
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G.P. Kumar et al. / Journal of Clinical Forensic Medicine 12 (2005) 271–273
grafting and nailing. He developed jaundice on the third postoperative day of the last surgical intervention, became icteric and died on 26th day of sustaining the injury. Biochemical investigations revealed impaired liver and renal functioning from the 21st day. The cause of death clinically was fulminant hepatitis, hepatic encephalopathy and acute renal failure with septicemia. 3. Autopsy findings The body of an adult male measuring 179 cm in length and 67 kg in weight showed the following signs of surgery: 1. A wound with skin graft over an area of 39 · 8 cm on the front of the left upper limb. 2. A sutured wound 5.5 cm in length over the tip of left shoulder. 3. An abraded wound (donor site of the graft) over the front of both the thighs. The pleural cavity contained 400 ml of yellow coloured fluid in the right and 300 ml in the left pleural cavity. The right lung was 750 gm and the left was 650 gm, both lungs were congested. Heart was 330 gm in weight and healthy. The peritoneal cavity contained 1000 ml of yellow coloured fluid with a shrunken liver weighing 700 gm, and an enlarged congested spleen of 440 gm. The kidneys were 200 gm (left) and 250 gm (right) in weight and were healthy. There was a fracture of left humerus in its distal third, left ulna in its upper third and left radius in its middle third. 4. Histopathological examination Lungs revealed enlarged edematous alveoli with dilated capillaries, lumen contained acute inflammatory cells and macrophages. Kidneys did not reveal any pathological changes. Spleen showed evidence of chronic venous congestion. Sections of the liver showed complete loss of architecture with massive necrosis of parenchyma and collapsed portal tracts. Bile stasis and chronic inflammatory cell infiltrate was also seen suggesting that features were consisting with halothane induced massive liver necrosis.
5. Discussion Halothane is a colourless liquid with a sweet smell and is highly volatile. It is mostly excreted unchanged by the lungs. At least 12% of an absorbed dose is metab-
olized to chlorine, bromine and trifluoroacetic acid with toxic intermediates suspecting of causing or contributing to hepatotoxicity. The risk of developing acute liver failure after halothane exposure was calculated between 1:8000 and 1:36000.2 The metabolic intermediates of halothane, trifluroacyl acid chloride, have been shown to cause acute liver necrosis in guinea pigs. Glutathione depleted animals developed severe hepatic injury on exposure to halothane indicating that glutathione would appear to help protect hepatocytes from covalent binding by reactive halothane biotransformation intermediates.6 Epoxide hydrolase and conjugation with glutathione provide protective mechanism to the hepatocytes. Genetic factors like constitutive levels of cytochrome P-450 isoenzymes, defects in protective mechanisms and acquired factors like malnutrition, chronic intake of alcohol or other microsomal enzyme inducers may be the reason for susceptibility of some patients.7 The safety of halothane has been the subject of several reports. In addition to causing liver necrosis, it is known to cause malignant hyperpyrexia. Halothane induced hepatitis can be avoided, only if its use is discontinued. Its overall safety when compared to other anesthetic agents, has compelled the anesthetists to continue its use.3 In this case report, the autopsy findings did not identify the cause of death, as the avulsion injury over the hand, for which the patient was admitted, was not sufficient in the ordinary course of nature to cause the death. The reasons for the sudden onset of ascites, shrunken liver and enlarged spleen were unaccounted for. The six postoperative episodes were uneventful, except for rise in body temperature and icterus. The laboratory investigations showed values consistant with hepatic and renal failure. The renal failure was due to hepatorenal syndrome, wherein the appearance of renal failure in patients with severe liver disease, in whom there were no intrinsic morphologic or functional causes for the renal failure.8 HBs Ag was negative. Perusal of the literature on hepatic injury revealed that many disorders might lead to hepatic failure. The great preponderance of liver disease and toxic drug injury is due to halothane.8 The diagnosis of halothane hepatitis is one of exclusion after traumatic causes, other hepatotoxic drugs, and infectious causes have been eliminated.1 Jaundice and fever following surgery, using halothane was reported. The temperature chart4 showing the onset of jaundice at the same time as temperature rise following halothane anesthesia were similar to the findings in our case report. The histopathological features of the liver (after ruling out other causes of liver damage) were consistent with the history of halothane toxicity, thus confirming that death was due to halothane induced hepatic necrosis.
G.P. Kumar et al. / Journal of Clinical Forensic Medicine 12 (2005) 271–273
Halothane administration should not be repeated if there is the slightest suspicion of even a mild reaction after the first anesthetic. Those requiring multiple anesthetics during a short period should not be given halothane. A second anesthetic with halothane should not be repeated within six months of the first.4
References 1. Ellenhom Mathew J, Barceloux Donald G. Diagnosis and treatment of human poisoning in medical toxicology. New York: Elsevier; 1988.
273
2. Weber P et al. Liver transplantation in halothane induced necrosis. Zentralbl Chir 1994;119(5):305–8. 3. David Zakhim, Boyer Thomas D. Hepatology in the textbook of liver disease. II ed. London: WB Saunders Company; 1990. 764–6 & 874–77. 4. Sheila Sherlock, James Dooley. Diseases of the liver and biliary system. X ed. Oxford: Blackwell Science Ltd; 1997. 353–54. 5. Macsween Roderick NM, Anthony Peter P. Pathology of the liver. Churchill Livingstone; 1979. 358–60. 6. Lind RC, Gandolfi AJ, Hall PM. A model for fatal halothane hepatitis in the guinea pig. Anaesthesiology 1994;81(2):478. p. 478–87. 7. Pessayre D, Larry D. Acute and chronic drug-induced hepatitis. Baillieres Clin Gastroenterol 1988;2(2):385–422. 8. Cortan Razmi S, Vinay Kumar, Robbins Stanley L. Robbins pathological basis of disease. V ed. Bangalore, India: Prism Books (Pvt) Ltd; 1994. 831–61.
O F
CLINICAL FORENSIC MEDICINE Journal of Clinical Forensic Medicine 12 (2005) 271–273 www.elsevier.com/locate/jcfm
Case report
Fulminant hepatic failure following halothane anaesthesia G. Pradeep Kumar a, Vrinda J. Bhat a
a,* ,
Vasantha Sowdi
b
Department of Forensic Medicine, Kasturba Medical College, Manipal 576104, India b Department of Pathology, KSHEMA, Mangalore, India Available online 8 August 2005
Abstract The forensic pathologist is responsible for determining the cause, manner and approximate time of death and injury. After recording the detailed description of the external and internal appearances, a short summary should be offered of the major positive findings and their relationship to the cause of death. In many cases this will be obvious, however when the findings are less clear-cut, or are multiple, then the alternatives should be discussed detailing the possible sequence of events and interpreting the findings in concluding the cause of death. It is essential to causally connect the autopsy findings to the cause of death. We present a case report wherein a person who sustained avulsion injury to his left hand in an industrial accident, died due to, fulminant hepatitis, hepatic encephalopathy and acute renal failure, having undergone six operations under general anesthesia with halothane during his stay in the hospital. 2004 Published by Elsevier Ltd and AFP. Keywords: Hepatic failure; Halothane toxicity; Hepatic encephalopathy
1. Introduction Risk factors for hepatotoxicity includes repeated exposure to halothane, prior history of jaundice, fever after halothane, obesity, middle-aged females and intra operative hypotension. Pre-existing liver disease probably does not increase susceptibility.1 Weber reported an unusual case of halothane induced hepatic failure in a 22 years old, wherein the typical risk factors of age over 40, female, obesity and previous exposure to halothane were not present.2 Hepatitis has also been described in three individuals who sniffed halothane repeatedly in order to obtain a drug high.3 Halothane hepatitis is much more frequent after multiple anesthetics. Jaundice appears about 10–28 days after a single exposure and 3–17 days after multiple exposures. This delay before jaundice is helpful in excluding *
Corresponding author. Tel.: +9844426463 (Mobile); fax: +91 820 2570061/2570062 E-mail address: [email protected] (V.J. Bhat). 1353-1131/$ - see front matter 2004 Published by Elsevier Ltd and AFP. doi:10.1016/j.jcfm.2004.10.019
other causes of postoperative icterus. If the patient becomes icteric, the mortality is very high.4 Fatal cases are characterized by progressively deepening jaundice, hemorrhagic phenomenon, ascites and coma. Prothrombin time is one of the best prognostic indicators; a prothrombin time of more than 20 s indicates a high likelihood of a fatal outcome.3 The hepatic injury is cytotoxic comprising of centrizonal necrosis or massive necrosis and minimal fatty changes. Inflammatory infiltration is much less prominent in halothane-induced injury than in viral hepatitis.5
2. Case report A 38-year-old male was admitted to Kasturba Medical College Hospital, Manipal for the treatment of an avulsion injury sustained on his left upper limb measuring 39 · 8 cm along with fractures of left humerus, radius and ulna. He was subjected to multiple (six) surgical procedures under general anesthesia using halothane over a period of 18 days for wound debridement,
272
G.P. Kumar et al. / Journal of Clinical Forensic Medicine 12 (2005) 271–273
grafting and nailing. He developed jaundice on the third postoperative day of the last surgical intervention, became icteric and died on 26th day of sustaining the injury. Biochemical investigations revealed impaired liver and renal functioning from the 21st day. The cause of death clinically was fulminant hepatitis, hepatic encephalopathy and acute renal failure with septicemia. 3. Autopsy findings The body of an adult male measuring 179 cm in length and 67 kg in weight showed the following signs of surgery: 1. A wound with skin graft over an area of 39 · 8 cm on the front of the left upper limb. 2. A sutured wound 5.5 cm in length over the tip of left shoulder. 3. An abraded wound (donor site of the graft) over the front of both the thighs. The pleural cavity contained 400 ml of yellow coloured fluid in the right and 300 ml in the left pleural cavity. The right lung was 750 gm and the left was 650 gm, both lungs were congested. Heart was 330 gm in weight and healthy. The peritoneal cavity contained 1000 ml of yellow coloured fluid with a shrunken liver weighing 700 gm, and an enlarged congested spleen of 440 gm. The kidneys were 200 gm (left) and 250 gm (right) in weight and were healthy. There was a fracture of left humerus in its distal third, left ulna in its upper third and left radius in its middle third. 4. Histopathological examination Lungs revealed enlarged edematous alveoli with dilated capillaries, lumen contained acute inflammatory cells and macrophages. Kidneys did not reveal any pathological changes. Spleen showed evidence of chronic venous congestion. Sections of the liver showed complete loss of architecture with massive necrosis of parenchyma and collapsed portal tracts. Bile stasis and chronic inflammatory cell infiltrate was also seen suggesting that features were consisting with halothane induced massive liver necrosis.
5. Discussion Halothane is a colourless liquid with a sweet smell and is highly volatile. It is mostly excreted unchanged by the lungs. At least 12% of an absorbed dose is metab-
olized to chlorine, bromine and trifluoroacetic acid with toxic intermediates suspecting of causing or contributing to hepatotoxicity. The risk of developing acute liver failure after halothane exposure was calculated between 1:8000 and 1:36000.2 The metabolic intermediates of halothane, trifluroacyl acid chloride, have been shown to cause acute liver necrosis in guinea pigs. Glutathione depleted animals developed severe hepatic injury on exposure to halothane indicating that glutathione would appear to help protect hepatocytes from covalent binding by reactive halothane biotransformation intermediates.6 Epoxide hydrolase and conjugation with glutathione provide protective mechanism to the hepatocytes. Genetic factors like constitutive levels of cytochrome P-450 isoenzymes, defects in protective mechanisms and acquired factors like malnutrition, chronic intake of alcohol or other microsomal enzyme inducers may be the reason for susceptibility of some patients.7 The safety of halothane has been the subject of several reports. In addition to causing liver necrosis, it is known to cause malignant hyperpyrexia. Halothane induced hepatitis can be avoided, only if its use is discontinued. Its overall safety when compared to other anesthetic agents, has compelled the anesthetists to continue its use.3 In this case report, the autopsy findings did not identify the cause of death, as the avulsion injury over the hand, for which the patient was admitted, was not sufficient in the ordinary course of nature to cause the death. The reasons for the sudden onset of ascites, shrunken liver and enlarged spleen were unaccounted for. The six postoperative episodes were uneventful, except for rise in body temperature and icterus. The laboratory investigations showed values consistant with hepatic and renal failure. The renal failure was due to hepatorenal syndrome, wherein the appearance of renal failure in patients with severe liver disease, in whom there were no intrinsic morphologic or functional causes for the renal failure.8 HBs Ag was negative. Perusal of the literature on hepatic injury revealed that many disorders might lead to hepatic failure. The great preponderance of liver disease and toxic drug injury is due to halothane.8 The diagnosis of halothane hepatitis is one of exclusion after traumatic causes, other hepatotoxic drugs, and infectious causes have been eliminated.1 Jaundice and fever following surgery, using halothane was reported. The temperature chart4 showing the onset of jaundice at the same time as temperature rise following halothane anesthesia were similar to the findings in our case report. The histopathological features of the liver (after ruling out other causes of liver damage) were consistent with the history of halothane toxicity, thus confirming that death was due to halothane induced hepatic necrosis.
G.P. Kumar et al. / Journal of Clinical Forensic Medicine 12 (2005) 271–273
Halothane administration should not be repeated if there is the slightest suspicion of even a mild reaction after the first anesthetic. Those requiring multiple anesthetics during a short period should not be given halothane. A second anesthetic with halothane should not be repeated within six months of the first.4
References 1. Ellenhom Mathew J, Barceloux Donald G. Diagnosis and treatment of human poisoning in medical toxicology. New York: Elsevier; 1988.
273
2. Weber P et al. Liver transplantation in halothane induced necrosis. Zentralbl Chir 1994;119(5):305–8. 3. David Zakhim, Boyer Thomas D. Hepatology in the textbook of liver disease. II ed. London: WB Saunders Company; 1990. 764–6 & 874–77. 4. Sheila Sherlock, James Dooley. Diseases of the liver and biliary system. X ed. Oxford: Blackwell Science Ltd; 1997. 353–54. 5. Macsween Roderick NM, Anthony Peter P. Pathology of the liver. Churchill Livingstone; 1979. 358–60. 6. Lind RC, Gandolfi AJ, Hall PM. A model for fatal halothane hepatitis in the guinea pig. Anaesthesiology 1994;81(2):478. p. 478–87. 7. Pessayre D, Larry D. Acute and chronic drug-induced hepatitis. Baillieres Clin Gastroenterol 1988;2(2):385–422. 8. Cortan Razmi S, Vinay Kumar, Robbins Stanley L. Robbins pathological basis of disease. V ed. Bangalore, India: Prism Books (Pvt) Ltd; 1994. 831–61.