Patel: The Fatal Paracetamol Dosage -
The Fatal Paracetamol Dosage -
how low can you go? 303
how low can you go?
F PATEL, DMJ Lecturer in Forensic Medicine, Guy's and St Thomas's Medical Schools (University of London), London Bridge, London. ABSTRACT
Popular texts and forensic literature pertaining to paracetamol toxicology advocate an acceptable minimal dose or lower limit of the blood level 'normally' associated with a fatal single overdose. A case of fatal, acute paracetamol poisoning from a minimal single dose, within the recommended therapeutic daily total and associated with a zero blood paracetamol levsl, is reported. It also emphasizes the common knowledge that the toxicological tabulated reference data available on fatal levels of most drugs is merely a guide. The proper interpretation of the analytical results thus requires the full consideration of the circumstances surrounding the death in each case. The clinico-pathophysiology and toxicology of paracetamol poisoning is briefly reviewed in an attempt to establish how low a fatal paracetamol dosage can go. The phenomenon of fatal dose and blood level is in a paracetamollimbo.
INTRODUCTION
Paracetamol (N acetyl-p-aminophenol), a paraaminophenol derivative with analgesic and antipyretic properties, whose probable mode of action involves inhibiting prostaglandin synthesis (Ellenhorn and Barceloux, 1988), is a widely and readily available household drug marketed under a plethora of proprietary names and which, in the recommended therapeutic dose of two 500mg tablets up to four times daily (for adults), is a very safe medicine (Polson et al., 1983). It has non-cumulative pharmacokinetics and is not subject to haemoconcentration, making it probably the safest antipyretic for children (Rumack, 1984). Overdosage, however, is currently a major cause of acute hepatic necrosis and death in Great Britain (Polson et al., 1983; Henry and Volans, 1984). Paracetamol-induced hepatotoxicity has become increasingly recognized, following the original British reports of large overdosage more than two decades ago
(Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986). Toxicity and fatalities in the adolescent group, i.e. over 12 years of age, compares with that in the adults (Rumack and Matthew, 1975). In children under the age of 12 years, the incidence of hepatotoxicity observed is low (Rumack, 1984) in spite of the frequent paracetamol ingestion in this age group, even when equivalent adult toxic blood level is achieved, suggesting a greater margin of safety than in the adolescent/adult group. This fact may explain the sparsity of the number of cases reported in the literature (Ellenhorn and Barceloux, 1988; Rumack, 1984). It has been suggested that if paracetamol were discovered and developed today then it would not be approved by the Committee on Safety of Medicine (Polson et al., 1983). The pharmacokinetic studies show that paracetamol is rapidly and completely absorbed from the gut, reaching a peak therapeutic concentration of 5 to 20 ~ml between one and four hours, and that it has a halflife of two to four hours (Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975; Smilkstein et al., 1988). The bulk of the absorbed paracetamol (about 90 per cent) is rapidly detoxified, mostly in the liver by sulphate and glucoronide conjugation, which under normal circumstances utilizes the endogenous glutathione stores (the former pathway being dominant in children - Ellenhorn and Barceloux, 1988) and is excreted mainly as mercaptourate and cysteine (Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975; Smilkstein et al., 1988). A small but important fraction (about five per cent) is bioconverted through the hepatic cytochrome
304
Moo. Sci. Law (1992) Vol. 32, No.4
P450 multifunction oxidase system to a potential hepatotoxic intermediate (N acetyl-p-benzoquinonimine), which would normally be removed by the hepatic glutathione (Ellenhorn and Barceloux, 1988; Polson et al., 1983; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975; Smilkstein et aI., 1988). In the overdose situation, saturation of the metabolic pathways occurs when a critical amount of glutathione store (about 70 per cent) is consumed, (Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986) and the excess hepatotoxic metabolite which accumulates may produce steatosis and hepatocellular necrosis (Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975; Smilkstein et al., 1988). The precise pathophysiological mechanisms of the organotoxicity are poorly understood (Rumack and Lovejoy, 1986). The hepatotoxicity may be potentiated by concomitant drugs, e.g. phenytoin or phenobarbitone, which induce the microsomal enzyme activity, or it may be enhanced when superimposed with conditions, e.g. chronic alcoholism, anorexia, vegetarian diet, poor nutritional or metabolic states and general debility, which can deplete the glutathione supply (Ellenhorn and Barceloux, 1988; Polson et al., 1983; Rumack and Lovejoy, 1986). Interestingly, acute alcohol intake may actually be hepatoprotective through competitive inhibition of the microsomal oxidative me-
tabolism (Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975). The relative safety in young children is unclear but may be due to the early vigorous emesis or the higher glutathione stores and difference in the metabolic pathway (Rumack, 1984). On the basis of experimental model, the depletion of the hepatic glutathione stores alone fails to account for the hepatotoxicity which causes hepatocellular necrosis (Ellenhorn and Barceloux, 1988; Rumack and Matthew, 1975; Smilkstein et al., 1988). It has also been suggested that the hepatic necrosis could be due to lipid peroxidation or oxidation of another group of liver enzymes, or even due to the prolonged elimination half life of paracetamol (Ellenhorn and Barceloux, 1988). Similarly, the renal bioconversion of the paracetamol within the kidneys may result in a nephrotoxic intermediate metabolite, which produces tubular or cortical necrosis and need not necessarily be associated with hepatic necrosis (Ellenhorn and Barceloux, 1988; Rumack and Matthew, 1975). Significant idiosyncrasy in susceptible individuals is observed when the blood paracetamollevel achieved is in the toxic range; only about 8 per cent of paracetamol overdosage cases manifest severe hepatotoxicity, even in the absence of appropriate treatment and 20 per cent remain 'hepato-immune' even though
Table 1. Major phases of the clinical presentation in acute paracetamol poisoning Clinical phases
Post-ingestion interval
Clinical presentation
Initial
2-24 hrs
Non-specific symptoms, e.g. nausea and vomiting (esp. in children). General malaise or remain asymptomatic
2
Latent
2 days
Apparent well being and improvement (subclinical LFT abnormality)
3
Delayed -
(hepatic stage)
3-5 days
(recovery stage)
8 days
Clinical improvement (return of LFT to normality)
4-18 days
Hepatocellular necrosis (increasingly abnormal LFT) Fatal outcome
(end stage)
Jaundice, coagulopathy, hypoglycaemia (gross LFT abnormality)
Patel: The Fatal Paracetamol Dosage -
the blood paracetamollevel is in the toxic range (Ellenhorn and Barceloux, 1988). Deaths from ensuing hepatic failure is only up to 2 per cent (Ellenhorn and Barceloux, 1988). The initial clinical presentation in acute paracetamol poisoning is non-specific and can be conveniently categorized into three major phases (Rumack and Lovejoy, 1986). The initial stage commences within a couple of hours of ingestion and lasts for approximately 24 hours, when there may be nausea and vomiting (more commonly in children) and general malaise, but the symptoms can be absent even after a large paracetamol overdose. The latent middle stage is ushered in at about 48 hours, when the victim shows an apparent improvement, giving a false sense of well-being in presence of sub-clinical liver function test (LFT) abnormality. Between three to five days post-ingestion, signs of jaundice, coagulopathy, hypoglycaemia and increasingly abnormal LFT herald the 'hepatic' stage with evidence of hepatocellular necrosis, which has a fatal outcome between four to eighteen days, or resolves in the 'recovery' stage on about the eighth day, with clinical improvement and a return of the LIT to normal (see Table l)(Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975). The treatment of choice is currently N-acetyl cysteine (NAC), which repletes glutathione (EIlenhorn and Barceloux, 1988; Smilkstein et al., 1988) and, as an effective antidote, prevents fatality if administered with urgency within ten hours of ingestion of paracetamol (Ellenhorn and Barceloux, 1988; Smilkstein et al., 1988). NAC appears to be ineffective beyond 15 to 24 hours (Ellenhorn and Barceloux, 1988) because the hepatoprotection is mediated by preventing the accumulation of intermediate metabolite through enhancing the glutathione stores and providing a glutathione substitute (Ellenhorn and Barceloux, 1988; Smilkstein et al., 1988). Other glutathione precursor drugs are methionine and cysteamine, which have been replaced by NAC. Following the introduction of NAC in Great Britain in 1973, the annual mortality figure has plummeted (Ellenhorn and Barceloux, 1988). Liver transplantation is the available option for
how low can you go? 305
fulminant liver failure or when conservative therapy fails. CASE REPORT
WL was a healthy 13 1;2 - year-old schoolgirl at the time of her demise. She lived with her parents and was the second of seven children. She had been referred to the district general hospital by her general practitioner with a history of nausea, vomiting and abdominal pains for the previous two days, and on the morning of her admission she was said to be retching. She was admitted on a Monday morning and the consultant paediatrician placed her in the children's isolation ward with a provisional diagnosis of gastroenteritis. The mother further elucidated that on the preceding Friday evening her daughter had taken five (500 mg) paracetamol tablets for a headache and that she had given her daughter some black coffee to induce vomiting. Her daughter was well enough the next day (Saturday) to attend an organized bonfire party that evening, and there was nothing untoward of any significance. However, on the Sunday her daughter was unwell and stayed in bed all day. During the early hours of the date of admission, her other children reported to her that their sister was crying out and was incoherent as well as moving oddly. There was no significant past medical history and no indication of a suicidal tendency or drug abuse. On clinical examination the patient was confused, disorientated and uncooperative with aggressive behaviour. She was noticed making repetitive licking movements of the lips. She was afebrile and normotensive but had mild tachycardia. Her pupils were equal and reacting to light and the general neurological examination was unremarkable. A specimen of venous blood and urine for drug assay was obtained soon after admission, which was approximately 60 hours post-ingestion of the paracetamol. The screening for blood salicylate and paracetamol using a standard kit was negative. The urine was also negative for a variety of common drugs and poisons which incl uded tricyclic antedepressan ts, phenothiazines, barbiturates, benzodiazepines,
306 Mad. Sci. Law (1992) Vol. 32, No.4
opiates, trichloro derivatives and paraquat. The standard routine laboratory investigations were unremarkable with the biochemical, haematological and microbiological parameters essentially within the normal range. The blood and urine samples were preserved. Some six hours post-admission, she was unconscious, unresponsive to painful stimuli and incontinent of urine. Her pupils were variable and there was an increased muscle tone and upgoing plantar reflex. Her general condition steadily deteriorated and over the next three hours became deeply comatose and many brainstem fits were observed. She was treated with Dexamethasone and mannitol. Just after twelve hours post-admission she was transferred to a local neurological unit where the lumbar puncture was unremarkable and the CT scan showed evidence of cerebral oedema. The repeat assay for paracetamol was negative. The prothrombin time was prolonged at 60 seconds (control 38). A working diagnosis of probable encephalopathy was considered, but the clinicians were unable to account for the severity and progressive neurological state. She was now in grade IV coma and electively put on an IPP ventilator and antibiotic cover. She had developed an extensor posture and was showing doll's eye movements. On the morning of the fourth day post-ingestion she was transferred to a major liver unit. She was now jaundiced, but no stigmata of chronic liver disease observed. A diagnosis of fulminant hepatic failure, probably due to paracetamol overdose, was made. A further battery of laboratory tests were made, which included investigations for copper, ceruloplasmin, autoantibodies, immunoglobulins, HBsAg, LFT and coagulopathy. The only abnormal results were an elevated serum bilirubin of 80 r-unolll (ref. range 3-20); alkaline phosphate 877 lUll (ref. range 30-85); AST 4740 lUll (ref. range 10-50); blood glucose 8.8 umol/l and the prothrombin time was 52 seconds (control 15), which fell to 39 seconds after an infusion of two litres of fresh, frozen plasma. An extradural ICP monitor was inserted under local anaesthesia and, in the next few hours, multiple episodes of rise in the ICP every
three to five minutes were recorded. These responded to thiopentone but not to mannitol and hyperventilation. The pupils became fixed and dilated and ischaemic brain damage consequent upon prolonged and severe raised intracranial pressure was suspected. Twenty-four hours following admission under the hepatologists, and on the fifth day post-ingestion, she died. The deceased was subject to a full postmortem examination for HM Coroner, performed by the author at 20 hours post mortem interval. Post-mortem examination The external examination showed a mildly jaundiced, healthy, well nourished and well developed teenage girl weighing 54 kg. There were various hospital therapeutic marks and no significant marks of violence or abuse. The internal examination showed a pale soft liver with coarse 'nutmeg' pattern of the cut surface (see Figure 1). There was widespread zonal hepatic necrosis. The brain was oedematous and showed evidence of moderately raised intracranial pressure. Coronal slicing revealed a 1cm acute pontine infarct and a smaller, more recent haemorrhagic infarct in the medulla. The cerebral blood vessels were healthy. The lungs showed gross pulmonary oedema and occasional pleural petechiae. The heart and other organs were healthy and unremarkable. The stomach contained brownish fluid with minute dark flecks in it,
Figure 1. Wedge of post-mortem liver showing zonal pallor with a coarse 'nutmeg' pattern.
Patel: The Fatal Paracetamol Dosage - how low can you go? 307
was no evidence of cholestasis or inflammatory cell reaction. There was relative sparing of the periportal hepatic parenchyma (Figures 2 and 3). The histological appearance was consistent with severe paracetamol hepatotoxicity within five days. In view of the circumstances surrounding the death, the cause of death was given as hepatic encephalopathy due to paracetamol poisoning. At the inquest, the mother of the deceased gave evidence that her late daughter had suffered from minor headaches for some weeks and that she had given permission for her to self-administer just two (500mg) tablets of paracetamol as usual. On the last occasion, the deceased had vomited and the mother, on observing a single paracetamol tablet in the vomitus, was prompted to question the actual paracetamol dosage ingested, and this was most definitely established as not more than five (500mg) paracetamol tablets. The deceased was described as a sensible, very reliable and generally very happy girl. The Coroner recorded a verdict of accidental death.
Figure 2. Microphotograph of liver showing diffuse paracetamol induced centrilobular necrosis (long arrow) with bridging necrosis (short arrow) and steatosis. H & Ex 100.
Figure 3. Microphotograph of liver showing a high power view of steatosis with microvacuolation (arrowed). H & E x 400.
DISCUSSION Studies have been made to relate the initial blood paracetamol level and eventual hepatotoxicity (Smilkstein et al., 1988). There appears to be a general tendency to 'fix' a convenient lower limit acceptable for a fatal overdosage, which does not allow for individual hypersensitivity to paracetamol, contrary to the common belief that, f01'"most drugs, the reference tabulated toxicology data in the popular texts and forensic literature based on reported cases for most drugs are not conclusive. The proper interpretation of the analytical results necessitates the full consideration of the circumstances surrounding the death. A single ingestion of up to 2g (4 x 500mg tablets) in adults, comparable to the case 'reported, is considered probably safe and, according to standard texts, a dose only several times this may be fatal (Rumack and Lovejoy, 1986; Rumack and Matthew, 1975).
308 Mad. Sci. Law (1992) Vol. 32, No.4
The minimum paracetamol dosage generally required to produce toxicity is variable; the actual toxic dosage being far greater (Rumack, 1984) than the figure often quoted of between 5g and 15g (10 to 30 x 500mg tablets) in adults and 150mg!kg body weight in children (Smilkstein et al., 1988). This would be equivalent to 8g (16 x 500mg tablets) in the case reported (body weight 54kg) and is at least double the amount of paracetamol questioned. The dosage of paracetamol absorbed by the deceased in the case reported may in fact be less than 2.5g (5 x 500mg tablets) due to the vomiting and incomplete ingestion. The fatal dose in adults and adolescents is in the range 12g to 25g (24 to 50 x 500mg tablets) and there are no reported cases of hepatotoxicity in healthy adults ingesting a single paracetamol dose at 125mg!kg, equivalent to about 8g (15 to 17 x 500mg tablets) (Ellenhorn and Barceloux, 1988). Fifty per cent of adults develop severe hepatocellular necrosis at 250mg!kg, equivalent to about 16g (30 to 35 x 500mg tablets), and this percentage rises to 100 per cent at 350mg!kg, equivalent to 23g (42 to 50 x 500mg tablets) (Ellenhorn and Barceloux, 1988). This is clearly in considerable excess of the 2.5g (5 x 500mg tablets) dose actually ingested in the case reported and in whom the minimum equivalent dose to produce hepatotoxicity, according to the above calculations, would be 6.5g (13 x 500mg tablets), which is obviously a considerable over-estimation as well. Deaths in the adult/adolescent group have been reported after paracetamol ingestion of 109 (20 x 500mg tablets) (Polson et al., 1983), and even this quantity is generally only accepted with enough scepticism to warrant prior consideration and exclusion of a contributing factor, such as general debility, other concomitant drugs, inaccuracy in analytic estimation or rapid fall of hepatotoxic blood paracetamollevels (polson et al., 1983; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975). Hitherto, no case of acute fatal paracetamol poisoning in a healthy adolescent attributed to ingestion of a single minimal dose and associated with a zero blood paracetamol level
(albeit a delayed presentation) but where the paracetamol dosage has been substantiated beyond any reasonable doubt by appropriate drug history and characteristic clinicopathological findings, has been reported. It is probable that cases of paracetamol overdose with low or undetectable levels do not get reported in the literature and are dismissed by attributing to contributory factors, such as inaccuracy in the drug history, in the collection of the sample, the analytical estimation, the estimation of the amount ingested and absorbed and possible individual idiosyncracy (Rumack and Lovejoy, 1986). This would then compound the variance inherent in the tabulated range of fatal levels which are necessarily compiled from reported fatal cases. Although a direct prediction of a fatal outcome or the estimation of paracetamol dose ingested cannot be made, the most reliable method of assessing the severity of paracetamol poisoning is from the blood levels, which reflect the pharmacological effect, in preference to guessing what must be ingested before toxicity can be expected (Polson et al., 1983; Rumack and Matthew, 1975). A series of the potential toxic range of blood paracetamollevels, which is based on the estimated time of paracetamol ingestion, aids in predicting the risk of hepatotoxicity by semilogarithmic plotting of these data to construct the Rumack-Matthew normogram (Ellenhorn and Barceloux, 1988; Smilkstein et al., 1988). The toxic levels are defined above a watershed line intersecting the plasma paracetamol levels of 200~ml at four hours; 50~ml at twelve hours; 25~ml at sixteen hours and 5!!g/ml at twenty four hours (Rumack and Lovejoy, 1986; Smilkstein et al., 1988). The level of 120~ml at four hours indicates non-toxic effects whereas above the line intersecting 300 ~ml at four hours and 75~ml at twelve hours indicates hepatotoxicity with inevitable hepatocellular necrosis (Rumack and Matthew, 1975; Smilkstein et al., 1988). The peak plasma paracetamollevel after a single acute ingestion is expected at four hours (Rumack and Lovejoy, 1986) and premature analysis within one to four hours post-ingestion of paracetamol may give a false negative result and this may also
Patel: The Fatal Paracetamol Dosage -
occur when the analytic estimation has been delayed as in the case reported. The halflife of the paracetamol elimination may be relied upon when the time interval of paracetamol ingestion is unknown or in doubt, by plotting the decay curve from a series of regular periodic estimates, provided the analysis is not delayed; a result of the half life of more than four hours is ominous (Polson et al., 1983). When the victim of paracetamol overdosage presents late (between three to five days), as in the case reported, the biochemical profile, especially the LFT, may show significantly abnormal AST and ALT in excess of 2,000 or 3,000 lUll, and compare with the AST of 4,000 lUll in the case reported. The prothrombin time is considered to be the best guide at this stage in assessing the severity and development of hepatic encephalopathy; a result of 25 seconds at 48 hours, or 40 seconds at 72 hours, is ominous (Ellenhorn and Barceloux, 1988), which compares with the average of 50 seconds at 72 to 96 hours in the case reported. The hepatic encephalopathy resulting in death is an uncommon complication occurring in only a small percentage of fatal cases (Rumack and Lovejoy, 1986). The hepatotoxicity becomes the most reliable feature when blood paracetamollevels are unreliable or undetectable and the diagnosis remains elusive (Rumack and Lovejoy, 1986; Rumack and Matthew, 1975), as in the case reported. The hepatocellular necrosis would be expected to ensue when a sufficient amount of paracetamol is absorbed, calculated to be about 15g (26 to 32 x 500mg tablets), to deplete the glutathione stores in a normal adult (Rumack and Lovejoy, 1986), yet the maximum paracetamol ingestion of only 2.5g (5 x 500mg tablets) by the deceased in the case reported was apparently adequate in the absence of other contributing factors. The paracetamolinduced hepatic micromorphology correlates with the clinical and laboratory parameters (Portmann et al., 1975). The hepatic necrosis is submassive with confluent centrizonal distribution, as in the case reported, and with additional mild changes such as cytoplasmic vacuolation, nuclear polymorphism and mitotic
how low can you go? 309
activity, steatosis and inflammatory cell infiltrate in the hepatic parenchyma, or within the necrotic areas, all of which have been observed in liver biopsies at five or six days postingestion of paracetamol (portmann et al., 1975). There may be evidence of reparative process at six to ten days post-ingestion ofparacetamol with the resultant reticulin collapse, mixed inflammatory cells and pigment laden macrophages (Portmann et al., 1975). The reactive changes relate to the degree of necrosis and the post-ingestion interval, becoming more evident at eight to ten days post-ingestion of paracetamol (Portmann et al., 1975). There may develop toxic hepatitis (Ellenhorn and Barceloux, 1988) and cholestasis and fatty microvacuolation which, in tandem with the hepatic regeneration, may resemble that in viral hepatitis (Portman et al., 1975). The centrilobular necrosis with confluent bridging necrosis, shown in Figures 2 and 3, in the areas of maximum multifunction oxidase activity, is fairly typical, and the associated steatosis in the case reported may resemble that in ethanol abuse. Similar micromorphology with hepatocellular necrosis and steatosis may be seen in poisoning with other drugs and toxins, namely chloroform, carbon tetrachloride, phosphorous, mushroom and aflatoxin poisoning (Ellenhom and Barceloux, 1988). Death may result either primarily or subsequent to fulminant hepatic failure and progressive encephalopathy and is inevitable when submassive hepatic necrosis destroys more than 60 per cent of the liver (Portmann et al., 1975). In hepatic encephalopathy there may be cerebral excitation or sudden coma from the cerebral oedema and raised intracranial pressure (Ellenhorn and Barceloux, 1988). The cerebral oedema was a striking feature in the case reported and a major contributing factor to death from hepatic encephalopathy which, incidentally, can be exacerbated if treatment with methionine is instituted beyond ten hours of the paracetamol overdosage (Ellenhorn and Barceloux, 1988). Death may also result from renal failure with development of hepatorenal syndrome in idiosyncratic individuals (Ellenhorn and Bar-
310 Med. Sci. Law (1992) Vol. 32, No.4
celoux, 1988). There may be morphological evidence of nephrotoxicity with acute tubular necrosis and cortical necrosis. There may be evidence of direct cardiotoxicity with focal myocardial necrosis, subendocardial haemorrhages or pericarditis causing death from cardiac failure (Ellenhorn and Barceloux, 1988; Polson et al., 1983; Rumack and Matthew, 1975). Rarely there may be evidence of pancreatitis (Ellenhorn and Barceloux, 1988). Very rarely an allergic reaction can manifest within an hour of paracetamol overdosage and death may result from anaphylactic shock due to the acute hypersensitivity causing bronchospasm and respiratory distress or hypotension and circulatory collapse (Stricker et al., 1985). The multisystem involvement, including pulmonary changes with adult respiratory distress syndrome, disseminated intravascular coagulation and opportunistic infections will manifest as fulminant hepatic failure. ACKNOWLEDGEMENT
I am grateful to Sir M. Levine (HM Coroner, Inner South London) for permission to report this case and to Dr P. Toseland for the invaluable toxicological analysis.
REFERENCES
Ellenhorn M. J. and Barceloux D. G. (1988) Acetaminophen (paracetamol). In: Ellenhorn M. J. and Barceloux D. G. Medical Toxicology: Diagnosis and Treatment of Human Poisoning. Amsterdam, Elsevier, Chapter 9. Henry J. and Volans G. (1984) Analgesic II: Paracetamol. Br. Med. J. 289, 907-8. Polson C. J., Green M. A and Lee M. R (1983) Analgesic and Antiinflammatory Agents. In: Polson C. J., Green M. A. and Lee M. R Clinical Toxicology, 3rd edition, London, Pitman, Chapter 5. Portmann B., Talbot 1. C., Day D. W., Davidson A. R, Murrey-Lyon 1. M. and Williams R. (1975) Histopathological changes in the liver following a paracetamol overdose: correlation with clinical and biological parameters. J. Pathol. 117, 169-81. Rumack B. H. and Matthew H. (1975) Acetaminophen poisoning and toxicity. Pediatrics 55, 871-6. Rumack B. H. (1984) Acetaminophen overdose in young children. Am. J. Dis. Child 138, 428-33. Rumack B. H. and Lovejoy F. H. (1986) Clinical Toxicology. In: (eds) Klaassen C. D., Amdur M. O. and Doull J., Casarett and Doull's Toxicology. The Basic Science of Poisons, 3rd edition, New York, Macmillan Publishing Co., Chapter 28. Smilkstein M. J., Knapp G. L., Kulig K. W. and Rumack B. H. (1988) Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. N. Eng. J. Med. 319,1557-62. Stricker B. H., Meyboom R H. and Lindquist M. (1985) Acute hypersensitivity reactions to paracetamol. Br. Med. J. 291, 938-9.
The Fatal Paracetamol Dosage -
how low can you go? 303
how low can you go?
F PATEL, DMJ Lecturer in Forensic Medicine, Guy's and St Thomas's Medical Schools (University of London), London Bridge, London. ABSTRACT
Popular texts and forensic literature pertaining to paracetamol toxicology advocate an acceptable minimal dose or lower limit of the blood level 'normally' associated with a fatal single overdose. A case of fatal, acute paracetamol poisoning from a minimal single dose, within the recommended therapeutic daily total and associated with a zero blood paracetamol levsl, is reported. It also emphasizes the common knowledge that the toxicological tabulated reference data available on fatal levels of most drugs is merely a guide. The proper interpretation of the analytical results thus requires the full consideration of the circumstances surrounding the death in each case. The clinico-pathophysiology and toxicology of paracetamol poisoning is briefly reviewed in an attempt to establish how low a fatal paracetamol dosage can go. The phenomenon of fatal dose and blood level is in a paracetamollimbo.
INTRODUCTION
Paracetamol (N acetyl-p-aminophenol), a paraaminophenol derivative with analgesic and antipyretic properties, whose probable mode of action involves inhibiting prostaglandin synthesis (Ellenhorn and Barceloux, 1988), is a widely and readily available household drug marketed under a plethora of proprietary names and which, in the recommended therapeutic dose of two 500mg tablets up to four times daily (for adults), is a very safe medicine (Polson et al., 1983). It has non-cumulative pharmacokinetics and is not subject to haemoconcentration, making it probably the safest antipyretic for children (Rumack, 1984). Overdosage, however, is currently a major cause of acute hepatic necrosis and death in Great Britain (Polson et al., 1983; Henry and Volans, 1984). Paracetamol-induced hepatotoxicity has become increasingly recognized, following the original British reports of large overdosage more than two decades ago
(Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986). Toxicity and fatalities in the adolescent group, i.e. over 12 years of age, compares with that in the adults (Rumack and Matthew, 1975). In children under the age of 12 years, the incidence of hepatotoxicity observed is low (Rumack, 1984) in spite of the frequent paracetamol ingestion in this age group, even when equivalent adult toxic blood level is achieved, suggesting a greater margin of safety than in the adolescent/adult group. This fact may explain the sparsity of the number of cases reported in the literature (Ellenhorn and Barceloux, 1988; Rumack, 1984). It has been suggested that if paracetamol were discovered and developed today then it would not be approved by the Committee on Safety of Medicine (Polson et al., 1983). The pharmacokinetic studies show that paracetamol is rapidly and completely absorbed from the gut, reaching a peak therapeutic concentration of 5 to 20 ~ml between one and four hours, and that it has a halflife of two to four hours (Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975; Smilkstein et al., 1988). The bulk of the absorbed paracetamol (about 90 per cent) is rapidly detoxified, mostly in the liver by sulphate and glucoronide conjugation, which under normal circumstances utilizes the endogenous glutathione stores (the former pathway being dominant in children - Ellenhorn and Barceloux, 1988) and is excreted mainly as mercaptourate and cysteine (Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975; Smilkstein et al., 1988). A small but important fraction (about five per cent) is bioconverted through the hepatic cytochrome
304
Moo. Sci. Law (1992) Vol. 32, No.4
P450 multifunction oxidase system to a potential hepatotoxic intermediate (N acetyl-p-benzoquinonimine), which would normally be removed by the hepatic glutathione (Ellenhorn and Barceloux, 1988; Polson et al., 1983; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975; Smilkstein et aI., 1988). In the overdose situation, saturation of the metabolic pathways occurs when a critical amount of glutathione store (about 70 per cent) is consumed, (Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986) and the excess hepatotoxic metabolite which accumulates may produce steatosis and hepatocellular necrosis (Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975; Smilkstein et al., 1988). The precise pathophysiological mechanisms of the organotoxicity are poorly understood (Rumack and Lovejoy, 1986). The hepatotoxicity may be potentiated by concomitant drugs, e.g. phenytoin or phenobarbitone, which induce the microsomal enzyme activity, or it may be enhanced when superimposed with conditions, e.g. chronic alcoholism, anorexia, vegetarian diet, poor nutritional or metabolic states and general debility, which can deplete the glutathione supply (Ellenhorn and Barceloux, 1988; Polson et al., 1983; Rumack and Lovejoy, 1986). Interestingly, acute alcohol intake may actually be hepatoprotective through competitive inhibition of the microsomal oxidative me-
tabolism (Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975). The relative safety in young children is unclear but may be due to the early vigorous emesis or the higher glutathione stores and difference in the metabolic pathway (Rumack, 1984). On the basis of experimental model, the depletion of the hepatic glutathione stores alone fails to account for the hepatotoxicity which causes hepatocellular necrosis (Ellenhorn and Barceloux, 1988; Rumack and Matthew, 1975; Smilkstein et al., 1988). It has also been suggested that the hepatic necrosis could be due to lipid peroxidation or oxidation of another group of liver enzymes, or even due to the prolonged elimination half life of paracetamol (Ellenhorn and Barceloux, 1988). Similarly, the renal bioconversion of the paracetamol within the kidneys may result in a nephrotoxic intermediate metabolite, which produces tubular or cortical necrosis and need not necessarily be associated with hepatic necrosis (Ellenhorn and Barceloux, 1988; Rumack and Matthew, 1975). Significant idiosyncrasy in susceptible individuals is observed when the blood paracetamollevel achieved is in the toxic range; only about 8 per cent of paracetamol overdosage cases manifest severe hepatotoxicity, even in the absence of appropriate treatment and 20 per cent remain 'hepato-immune' even though
Table 1. Major phases of the clinical presentation in acute paracetamol poisoning Clinical phases
Post-ingestion interval
Clinical presentation
Initial
2-24 hrs
Non-specific symptoms, e.g. nausea and vomiting (esp. in children). General malaise or remain asymptomatic
2
Latent
2 days
Apparent well being and improvement (subclinical LFT abnormality)
3
Delayed -
(hepatic stage)
3-5 days
(recovery stage)
8 days
Clinical improvement (return of LFT to normality)
4-18 days
Hepatocellular necrosis (increasingly abnormal LFT) Fatal outcome
(end stage)
Jaundice, coagulopathy, hypoglycaemia (gross LFT abnormality)
Patel: The Fatal Paracetamol Dosage -
the blood paracetamollevel is in the toxic range (Ellenhorn and Barceloux, 1988). Deaths from ensuing hepatic failure is only up to 2 per cent (Ellenhorn and Barceloux, 1988). The initial clinical presentation in acute paracetamol poisoning is non-specific and can be conveniently categorized into three major phases (Rumack and Lovejoy, 1986). The initial stage commences within a couple of hours of ingestion and lasts for approximately 24 hours, when there may be nausea and vomiting (more commonly in children) and general malaise, but the symptoms can be absent even after a large paracetamol overdose. The latent middle stage is ushered in at about 48 hours, when the victim shows an apparent improvement, giving a false sense of well-being in presence of sub-clinical liver function test (LFT) abnormality. Between three to five days post-ingestion, signs of jaundice, coagulopathy, hypoglycaemia and increasingly abnormal LFT herald the 'hepatic' stage with evidence of hepatocellular necrosis, which has a fatal outcome between four to eighteen days, or resolves in the 'recovery' stage on about the eighth day, with clinical improvement and a return of the LIT to normal (see Table l)(Ellenhorn and Barceloux, 1988; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975). The treatment of choice is currently N-acetyl cysteine (NAC), which repletes glutathione (EIlenhorn and Barceloux, 1988; Smilkstein et al., 1988) and, as an effective antidote, prevents fatality if administered with urgency within ten hours of ingestion of paracetamol (Ellenhorn and Barceloux, 1988; Smilkstein et al., 1988). NAC appears to be ineffective beyond 15 to 24 hours (Ellenhorn and Barceloux, 1988) because the hepatoprotection is mediated by preventing the accumulation of intermediate metabolite through enhancing the glutathione stores and providing a glutathione substitute (Ellenhorn and Barceloux, 1988; Smilkstein et al., 1988). Other glutathione precursor drugs are methionine and cysteamine, which have been replaced by NAC. Following the introduction of NAC in Great Britain in 1973, the annual mortality figure has plummeted (Ellenhorn and Barceloux, 1988). Liver transplantation is the available option for
how low can you go? 305
fulminant liver failure or when conservative therapy fails. CASE REPORT
WL was a healthy 13 1;2 - year-old schoolgirl at the time of her demise. She lived with her parents and was the second of seven children. She had been referred to the district general hospital by her general practitioner with a history of nausea, vomiting and abdominal pains for the previous two days, and on the morning of her admission she was said to be retching. She was admitted on a Monday morning and the consultant paediatrician placed her in the children's isolation ward with a provisional diagnosis of gastroenteritis. The mother further elucidated that on the preceding Friday evening her daughter had taken five (500 mg) paracetamol tablets for a headache and that she had given her daughter some black coffee to induce vomiting. Her daughter was well enough the next day (Saturday) to attend an organized bonfire party that evening, and there was nothing untoward of any significance. However, on the Sunday her daughter was unwell and stayed in bed all day. During the early hours of the date of admission, her other children reported to her that their sister was crying out and was incoherent as well as moving oddly. There was no significant past medical history and no indication of a suicidal tendency or drug abuse. On clinical examination the patient was confused, disorientated and uncooperative with aggressive behaviour. She was noticed making repetitive licking movements of the lips. She was afebrile and normotensive but had mild tachycardia. Her pupils were equal and reacting to light and the general neurological examination was unremarkable. A specimen of venous blood and urine for drug assay was obtained soon after admission, which was approximately 60 hours post-ingestion of the paracetamol. The screening for blood salicylate and paracetamol using a standard kit was negative. The urine was also negative for a variety of common drugs and poisons which incl uded tricyclic antedepressan ts, phenothiazines, barbiturates, benzodiazepines,
306 Mad. Sci. Law (1992) Vol. 32, No.4
opiates, trichloro derivatives and paraquat. The standard routine laboratory investigations were unremarkable with the biochemical, haematological and microbiological parameters essentially within the normal range. The blood and urine samples were preserved. Some six hours post-admission, she was unconscious, unresponsive to painful stimuli and incontinent of urine. Her pupils were variable and there was an increased muscle tone and upgoing plantar reflex. Her general condition steadily deteriorated and over the next three hours became deeply comatose and many brainstem fits were observed. She was treated with Dexamethasone and mannitol. Just after twelve hours post-admission she was transferred to a local neurological unit where the lumbar puncture was unremarkable and the CT scan showed evidence of cerebral oedema. The repeat assay for paracetamol was negative. The prothrombin time was prolonged at 60 seconds (control 38). A working diagnosis of probable encephalopathy was considered, but the clinicians were unable to account for the severity and progressive neurological state. She was now in grade IV coma and electively put on an IPP ventilator and antibiotic cover. She had developed an extensor posture and was showing doll's eye movements. On the morning of the fourth day post-ingestion she was transferred to a major liver unit. She was now jaundiced, but no stigmata of chronic liver disease observed. A diagnosis of fulminant hepatic failure, probably due to paracetamol overdose, was made. A further battery of laboratory tests were made, which included investigations for copper, ceruloplasmin, autoantibodies, immunoglobulins, HBsAg, LFT and coagulopathy. The only abnormal results were an elevated serum bilirubin of 80 r-unolll (ref. range 3-20); alkaline phosphate 877 lUll (ref. range 30-85); AST 4740 lUll (ref. range 10-50); blood glucose 8.8 umol/l and the prothrombin time was 52 seconds (control 15), which fell to 39 seconds after an infusion of two litres of fresh, frozen plasma. An extradural ICP monitor was inserted under local anaesthesia and, in the next few hours, multiple episodes of rise in the ICP every
three to five minutes were recorded. These responded to thiopentone but not to mannitol and hyperventilation. The pupils became fixed and dilated and ischaemic brain damage consequent upon prolonged and severe raised intracranial pressure was suspected. Twenty-four hours following admission under the hepatologists, and on the fifth day post-ingestion, she died. The deceased was subject to a full postmortem examination for HM Coroner, performed by the author at 20 hours post mortem interval. Post-mortem examination The external examination showed a mildly jaundiced, healthy, well nourished and well developed teenage girl weighing 54 kg. There were various hospital therapeutic marks and no significant marks of violence or abuse. The internal examination showed a pale soft liver with coarse 'nutmeg' pattern of the cut surface (see Figure 1). There was widespread zonal hepatic necrosis. The brain was oedematous and showed evidence of moderately raised intracranial pressure. Coronal slicing revealed a 1cm acute pontine infarct and a smaller, more recent haemorrhagic infarct in the medulla. The cerebral blood vessels were healthy. The lungs showed gross pulmonary oedema and occasional pleural petechiae. The heart and other organs were healthy and unremarkable. The stomach contained brownish fluid with minute dark flecks in it,
Figure 1. Wedge of post-mortem liver showing zonal pallor with a coarse 'nutmeg' pattern.
Patel: The Fatal Paracetamol Dosage - how low can you go? 307
was no evidence of cholestasis or inflammatory cell reaction. There was relative sparing of the periportal hepatic parenchyma (Figures 2 and 3). The histological appearance was consistent with severe paracetamol hepatotoxicity within five days. In view of the circumstances surrounding the death, the cause of death was given as hepatic encephalopathy due to paracetamol poisoning. At the inquest, the mother of the deceased gave evidence that her late daughter had suffered from minor headaches for some weeks and that she had given permission for her to self-administer just two (500mg) tablets of paracetamol as usual. On the last occasion, the deceased had vomited and the mother, on observing a single paracetamol tablet in the vomitus, was prompted to question the actual paracetamol dosage ingested, and this was most definitely established as not more than five (500mg) paracetamol tablets. The deceased was described as a sensible, very reliable and generally very happy girl. The Coroner recorded a verdict of accidental death.
Figure 2. Microphotograph of liver showing diffuse paracetamol induced centrilobular necrosis (long arrow) with bridging necrosis (short arrow) and steatosis. H & Ex 100.
Figure 3. Microphotograph of liver showing a high power view of steatosis with microvacuolation (arrowed). H & E x 400.
DISCUSSION Studies have been made to relate the initial blood paracetamol level and eventual hepatotoxicity (Smilkstein et al., 1988). There appears to be a general tendency to 'fix' a convenient lower limit acceptable for a fatal overdosage, which does not allow for individual hypersensitivity to paracetamol, contrary to the common belief that, f01'"most drugs, the reference tabulated toxicology data in the popular texts and forensic literature based on reported cases for most drugs are not conclusive. The proper interpretation of the analytical results necessitates the full consideration of the circumstances surrounding the death. A single ingestion of up to 2g (4 x 500mg tablets) in adults, comparable to the case 'reported, is considered probably safe and, according to standard texts, a dose only several times this may be fatal (Rumack and Lovejoy, 1986; Rumack and Matthew, 1975).
308 Mad. Sci. Law (1992) Vol. 32, No.4
The minimum paracetamol dosage generally required to produce toxicity is variable; the actual toxic dosage being far greater (Rumack, 1984) than the figure often quoted of between 5g and 15g (10 to 30 x 500mg tablets) in adults and 150mg!kg body weight in children (Smilkstein et al., 1988). This would be equivalent to 8g (16 x 500mg tablets) in the case reported (body weight 54kg) and is at least double the amount of paracetamol questioned. The dosage of paracetamol absorbed by the deceased in the case reported may in fact be less than 2.5g (5 x 500mg tablets) due to the vomiting and incomplete ingestion. The fatal dose in adults and adolescents is in the range 12g to 25g (24 to 50 x 500mg tablets) and there are no reported cases of hepatotoxicity in healthy adults ingesting a single paracetamol dose at 125mg!kg, equivalent to about 8g (15 to 17 x 500mg tablets) (Ellenhorn and Barceloux, 1988). Fifty per cent of adults develop severe hepatocellular necrosis at 250mg!kg, equivalent to about 16g (30 to 35 x 500mg tablets), and this percentage rises to 100 per cent at 350mg!kg, equivalent to 23g (42 to 50 x 500mg tablets) (Ellenhorn and Barceloux, 1988). This is clearly in considerable excess of the 2.5g (5 x 500mg tablets) dose actually ingested in the case reported and in whom the minimum equivalent dose to produce hepatotoxicity, according to the above calculations, would be 6.5g (13 x 500mg tablets), which is obviously a considerable over-estimation as well. Deaths in the adult/adolescent group have been reported after paracetamol ingestion of 109 (20 x 500mg tablets) (Polson et al., 1983), and even this quantity is generally only accepted with enough scepticism to warrant prior consideration and exclusion of a contributing factor, such as general debility, other concomitant drugs, inaccuracy in analytic estimation or rapid fall of hepatotoxic blood paracetamollevels (polson et al., 1983; Rumack and Lovejoy, 1986; Rumack and Matthew, 1975). Hitherto, no case of acute fatal paracetamol poisoning in a healthy adolescent attributed to ingestion of a single minimal dose and associated with a zero blood paracetamol level
(albeit a delayed presentation) but where the paracetamol dosage has been substantiated beyond any reasonable doubt by appropriate drug history and characteristic clinicopathological findings, has been reported. It is probable that cases of paracetamol overdose with low or undetectable levels do not get reported in the literature and are dismissed by attributing to contributory factors, such as inaccuracy in the drug history, in the collection of the sample, the analytical estimation, the estimation of the amount ingested and absorbed and possible individual idiosyncracy (Rumack and Lovejoy, 1986). This would then compound the variance inherent in the tabulated range of fatal levels which are necessarily compiled from reported fatal cases. Although a direct prediction of a fatal outcome or the estimation of paracetamol dose ingested cannot be made, the most reliable method of assessing the severity of paracetamol poisoning is from the blood levels, which reflect the pharmacological effect, in preference to guessing what must be ingested before toxicity can be expected (Polson et al., 1983; Rumack and Matthew, 1975). A series of the potential toxic range of blood paracetamollevels, which is based on the estimated time of paracetamol ingestion, aids in predicting the risk of hepatotoxicity by semilogarithmic plotting of these data to construct the Rumack-Matthew normogram (Ellenhorn and Barceloux, 1988; Smilkstein et al., 1988). The toxic levels are defined above a watershed line intersecting the plasma paracetamol levels of 200~ml at four hours; 50~ml at twelve hours; 25~ml at sixteen hours and 5!!g/ml at twenty four hours (Rumack and Lovejoy, 1986; Smilkstein et al., 1988). The level of 120~ml at four hours indicates non-toxic effects whereas above the line intersecting 300 ~ml at four hours and 75~ml at twelve hours indicates hepatotoxicity with inevitable hepatocellular necrosis (Rumack and Matthew, 1975; Smilkstein et al., 1988). The peak plasma paracetamollevel after a single acute ingestion is expected at four hours (Rumack and Lovejoy, 1986) and premature analysis within one to four hours post-ingestion of paracetamol may give a false negative result and this may also
Patel: The Fatal Paracetamol Dosage -
occur when the analytic estimation has been delayed as in the case reported. The halflife of the paracetamol elimination may be relied upon when the time interval of paracetamol ingestion is unknown or in doubt, by plotting the decay curve from a series of regular periodic estimates, provided the analysis is not delayed; a result of the half life of more than four hours is ominous (Polson et al., 1983). When the victim of paracetamol overdosage presents late (between three to five days), as in the case reported, the biochemical profile, especially the LFT, may show significantly abnormal AST and ALT in excess of 2,000 or 3,000 lUll, and compare with the AST of 4,000 lUll in the case reported. The prothrombin time is considered to be the best guide at this stage in assessing the severity and development of hepatic encephalopathy; a result of 25 seconds at 48 hours, or 40 seconds at 72 hours, is ominous (Ellenhorn and Barceloux, 1988), which compares with the average of 50 seconds at 72 to 96 hours in the case reported. The hepatic encephalopathy resulting in death is an uncommon complication occurring in only a small percentage of fatal cases (Rumack and Lovejoy, 1986). The hepatotoxicity becomes the most reliable feature when blood paracetamollevels are unreliable or undetectable and the diagnosis remains elusive (Rumack and Lovejoy, 1986; Rumack and Matthew, 1975), as in the case reported. The hepatocellular necrosis would be expected to ensue when a sufficient amount of paracetamol is absorbed, calculated to be about 15g (26 to 32 x 500mg tablets), to deplete the glutathione stores in a normal adult (Rumack and Lovejoy, 1986), yet the maximum paracetamol ingestion of only 2.5g (5 x 500mg tablets) by the deceased in the case reported was apparently adequate in the absence of other contributing factors. The paracetamolinduced hepatic micromorphology correlates with the clinical and laboratory parameters (Portmann et al., 1975). The hepatic necrosis is submassive with confluent centrizonal distribution, as in the case reported, and with additional mild changes such as cytoplasmic vacuolation, nuclear polymorphism and mitotic
how low can you go? 309
activity, steatosis and inflammatory cell infiltrate in the hepatic parenchyma, or within the necrotic areas, all of which have been observed in liver biopsies at five or six days postingestion of paracetamol (portmann et al., 1975). There may be evidence of reparative process at six to ten days post-ingestion ofparacetamol with the resultant reticulin collapse, mixed inflammatory cells and pigment laden macrophages (Portmann et al., 1975). The reactive changes relate to the degree of necrosis and the post-ingestion interval, becoming more evident at eight to ten days post-ingestion of paracetamol (Portmann et al., 1975). There may develop toxic hepatitis (Ellenhorn and Barceloux, 1988) and cholestasis and fatty microvacuolation which, in tandem with the hepatic regeneration, may resemble that in viral hepatitis (Portman et al., 1975). The centrilobular necrosis with confluent bridging necrosis, shown in Figures 2 and 3, in the areas of maximum multifunction oxidase activity, is fairly typical, and the associated steatosis in the case reported may resemble that in ethanol abuse. Similar micromorphology with hepatocellular necrosis and steatosis may be seen in poisoning with other drugs and toxins, namely chloroform, carbon tetrachloride, phosphorous, mushroom and aflatoxin poisoning (Ellenhom and Barceloux, 1988). Death may result either primarily or subsequent to fulminant hepatic failure and progressive encephalopathy and is inevitable when submassive hepatic necrosis destroys more than 60 per cent of the liver (Portmann et al., 1975). In hepatic encephalopathy there may be cerebral excitation or sudden coma from the cerebral oedema and raised intracranial pressure (Ellenhorn and Barceloux, 1988). The cerebral oedema was a striking feature in the case reported and a major contributing factor to death from hepatic encephalopathy which, incidentally, can be exacerbated if treatment with methionine is instituted beyond ten hours of the paracetamol overdosage (Ellenhorn and Barceloux, 1988). Death may also result from renal failure with development of hepatorenal syndrome in idiosyncratic individuals (Ellenhorn and Bar-
310 Med. Sci. Law (1992) Vol. 32, No.4
celoux, 1988). There may be morphological evidence of nephrotoxicity with acute tubular necrosis and cortical necrosis. There may be evidence of direct cardiotoxicity with focal myocardial necrosis, subendocardial haemorrhages or pericarditis causing death from cardiac failure (Ellenhorn and Barceloux, 1988; Polson et al., 1983; Rumack and Matthew, 1975). Rarely there may be evidence of pancreatitis (Ellenhorn and Barceloux, 1988). Very rarely an allergic reaction can manifest within an hour of paracetamol overdosage and death may result from anaphylactic shock due to the acute hypersensitivity causing bronchospasm and respiratory distress or hypotension and circulatory collapse (Stricker et al., 1985). The multisystem involvement, including pulmonary changes with adult respiratory distress syndrome, disseminated intravascular coagulation and opportunistic infections will manifest as fulminant hepatic failure. ACKNOWLEDGEMENT
I am grateful to Sir M. Levine (HM Coroner, Inner South London) for permission to report this case and to Dr P. Toseland for the invaluable toxicological analysis.
REFERENCES
Ellenhorn M. J. and Barceloux D. G. (1988) Acetaminophen (paracetamol). In: Ellenhorn M. J. and Barceloux D. G. Medical Toxicology: Diagnosis and Treatment of Human Poisoning. Amsterdam, Elsevier, Chapter 9. Henry J. and Volans G. (1984) Analgesic II: Paracetamol. Br. Med. J. 289, 907-8. Polson C. J., Green M. A and Lee M. R (1983) Analgesic and Antiinflammatory Agents. In: Polson C. J., Green M. A. and Lee M. R Clinical Toxicology, 3rd edition, London, Pitman, Chapter 5. Portmann B., Talbot 1. C., Day D. W., Davidson A. R, Murrey-Lyon 1. M. and Williams R. (1975) Histopathological changes in the liver following a paracetamol overdose: correlation with clinical and biological parameters. J. Pathol. 117, 169-81. Rumack B. H. and Matthew H. (1975) Acetaminophen poisoning and toxicity. Pediatrics 55, 871-6. Rumack B. H. (1984) Acetaminophen overdose in young children. Am. J. Dis. Child 138, 428-33. Rumack B. H. and Lovejoy F. H. (1986) Clinical Toxicology. In: (eds) Klaassen C. D., Amdur M. O. and Doull J., Casarett and Doull's Toxicology. The Basic Science of Poisons, 3rd edition, New York, Macmillan Publishing Co., Chapter 28. Smilkstein M. J., Knapp G. L., Kulig K. W. and Rumack B. H. (1988) Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. N. Eng. J. Med. 319,1557-62. Stricker B. H., Meyboom R H. and Lindquist M. (1985) Acute hypersensitivity reactions to paracetamol. Br. Med. J. 291, 938-9.
