Lesson of the week: Deaths from low dose paracetamol poisoning

Case reports

Case 1—A 16 year old girl presented to her accident and emergency department four hours after ingesting 20 paracetamol tablets (10 g). She had no additional risk factors for enhanced hepatotoxicity. Her serum paracetamol concentration was 156 mg/l, and she was discharged after receiving 50 g of a proprietary formulation of activated charcoal. Over the next two days her family noted that she was becoming progressively confused and drowsy. She represented 48 hours after the initial assessment. On examination she was encephalopathic (Glasgow coma score 9), icteric, dehydrated, and tachypnoeic, and had an international normalised ratio of 6.3 and an arterial pH of 7.16. Investigations showed serum concentrations as follows: alanine aminotransferase >7 500 IU/l, bilirubin 87 µmol/l, glucose 1.9 mmol/l, and creatinine 146 µmol/l. She was started on an acetylcysteine infusion and treatment for acute liver failure, and was electively ventilated before transfer. She continued to deteriorate with rising intracranial pressure, and underwent a total hepatectomy. A liver transplant was carried out 36 hours later but as there was no recovery of brain stem function by 10 days after the overdose ventilatory support was withdrawn.

Case 2 —A 24 year old man presented to his accident and emergency department within four hours of ingesting 64 paracetamol tablets (32 g). He had a history of alcohol misuse (about 100 units per week). Four hours after the overdose he had a serum paracetamol concentration of 178 mg/l. He was given 50 g of activated charcoal and discharged. Over the next two days he had worsening abdominal pain and was vomiting. He represented 48 hours after the overdose. He was retching profusely, was icteric, and had bilateral subconjunctival haemorrhages. Investigations showed a serum glucose concentration of 2.1 mmol/l, a serum creatinine concentration of 218 µmol/l, an international normalised ratio of 8, and an arterial pH of 7.3. He was started on acetylcysteine before transfer and, despite developing grade 3 encephalopathy, his liver recovered to the extent that his international normalised ratio fell to 2.2. His progress was complicated by oliguric renal failure, lobar pneumonia, and ventricular arrhythmias. He died from septicaemia and persistent multifocal seizures on the sixth day after the overdose.

Case 3 —A 38 year old man presented to his accident and emergency department after ingesting 50 paracetamol tablets (25 g). He had no apparent risk factors for enhanced hepatotoxicity. Four and a quarter hours after the overdose his serum paracetamol concentration was 178 mg/l. He was admitted to a psychiatric ward for further observation. Over the next two days he became increasingly confused and aggressive and was noted to be icteric and had periorbital bruising. Investigations showed a serum glucose concentration of <1 mmol/l, a serum creatinine concentration of 435 µmol/l, an international normalised ratio of 6, and an arterial pH of 7.45. He was electively ventilated and transferred. He continued to deteriorate as a result of pneumonia, fungal sepsis, and increasing intracranial pressure. He died on the 10th day after the overdose.

Case 4 —A 34 year old woman presented to her accident and emergency department after ingesting 30 paracetamol tablets (15 g). She had no known risk factors for enhanced hepatotoxicity. Six hours after the overdose her serum paracetamol concentration was 122 mg/l. After psychiatric review she was discharged but represented two days later with a 24 hour history of malaise, vomiting, and abdominal pain. At that time she was fully alert and orientated but clinically dehydrated. Her pulse was 92 sinus rhythm and she had a blood pressure of 90/60 mm Hg, diffuse abdominal tenderness, an international normalised ratio of 10, and an arterial pH of 7.4. Investigations showed serum concentrations as follows: glucose 2 mmol/l, sodium 130 mmol/l, potassium 4.5 mmol/l, urea 11.9 mmol/l, and creatinine 229 µmol/l. She was transferred but despite full supportive treatment died on the 15th day after the overdose while awaiting liver transplant.

Discussion

The course and outcome of the four case histories raise questions about the initial management of these patients. Although the patients were medically reviewed within six hours of overdose, acetylcysteine was not given and three patients were discharged with no follow up.

The history of alcohol misuse in case 2 suggests that his serum paracetamol concentration of 178 mg/l four hours after the overdose should have been compared with the high risk line (100 mg/l at four hours) rather than the standard treatment nomogram. Cases 1, 3, and 4 had no known additional risk factors for enhanced hepatotoxicity, and the timing of the overdose in these cases was thought to be accurate, but despite this the patients developed acute liver failure within 48 hours of discharge. The most likely explanation is an error in the timing of the overdoses. If the overdoses in cases 1 and 4 had been taken two hours earlier an error in timing would have given non-toxic concentrations (156 mg/l at four hours and 122 mg/l at six hours) above the treatment line at presentation whereas a one hour error in case 3 would have had the same effect.

Alternatively the rapid onset of acute liver failure might have been the consequence of an overdose before the presenting overdose, or the patients may have been more susceptible to the hepatotoxic effects of paracetamol. Wide intersubject and ethnic differences in the metabolism of paracetamol have been reported: one report showed a 60-fold range in the metabolic activation of paracetamol between subjects, and a threefold variation in glucuronide and sulphate conjugation,18 suggesting a subgroup of patients profoundly more susceptible to the hepatotoxic effects of paracetamol. This has never, however, been proved in the context of an overdose.