- Email: [email protected]
Paracetamol (acetaminophen)
SPECIFIC SUBSTANCES
Prostaglandin endoperoxide synthase, N-deacetylase and P450-dependent mixed-function oxidases are involved in paracetamol-induced renal damage.2
Paracetamol (acetaminophen)
Prediction of liver damage D Nicholas Bateman
The severity of paracetamol poisoning is dose-related. If a patient has ingested <150 mg/kg it is unlikely that serious toxicity will occur, whereas if a patient has ingested >150 mg/kg, the overdose is potentially serious. If the patient has risk factors such as malnutrition, acute starvation or chronic ethanol ingestion and is receiving enzyme-inducing drugs, toxicity is more likely.3 However, a single measurement of the plasma paracetamol concentration >4 hours after ingestion is a more accurate predictor of liver damage than dose alone. For example, in patients in whom the concentration lies above the line drawn from 200 mg/litre at 4 hourse30 mg/litre at 15 hours, 60% are likely to sustain liver damage (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1000 IU/litre) unless acetylcysteine is given.
Allister Vale
Abstract Paracetamol poisoning is common. If untreated, liver and/or renal failure can develop. The administration of acetylcysteine within 8e10 hours of overdose will minimize or prevent hepatic damage and ensure survival irrespective of the magnitude of the ingestion. Important prognostic factors are the international normalized ratio, pH and plasma creatinine concentration.
Keywords Acetylcysteine; hepatic encephalopathy hypophosphataemia; INR; pH; plasma creatinine; renal failure
Features Introduction Following ingestion of an overdose of paracetamol, patients can develop anorexia, nausea and vomiting, or can remain asymptomatic for the first 24 hours. Liver damage is not usually detectable by routine liver function tests until at least 18 hours after ingestion of the drug, and hepatic tenderness and abdominal pain are seldom exhibited before the second day.4 Maximum liver damage, as assessed by plasma ALT or AST activity or prothrombin time (international normalized ratio (INR)), usually occurs 72e96 hours after ingestion but may be more rapid in severe cases. Hepatic failure (manifest by jaundice and encephalopathy) can then develop between the third and fifth days; the rate of clinical deterioration reflects the severity of the overdose. More usually, prolongation of prothrombin time (INR) and a marked increase in ALT/AST activity occur without development of fulminant hepatic failure. Rate of rise of ALT correlates with severity of liver injury,5 but the magnitude of the rise is not prognostic. Renal failure as a result of acute tubular necrosis develops in about 25% of patients with severe hepatic damage and in a few without evidence of serious disturbance of liver function. Hypophosphataemia6 and hypokalaemia7 can occur due to paracetamol-induced renal tubular damage. Renal failure at first presentation is associated with a 50% mortality rate.8 Other features, including hypoglycaemia, pancreatitis, gastrointestinal haemorrhage and cerebral oedema, can occur with hepatic failure from any cause and are not direct consequences of paracetamol toxicity.
Up to 40% of all admissions to hospital with self-poisoning in the UK involve paracetamol. Patients are predominantly young, and over half have taken a previous overdose. Most deaths are associated with deliberate self-poisoning and late presentation, but therapeutic misadventures can occur in both adults and children.
Mechanisms of toxicity In therapeutic doses, 60e90% of the drug is metabolized by conjugation to form paracetamol glucuronide and sulfate; 5e10% is oxidized by mixed-function oxidase enzymes (principally CYP2E1) to form highly reactive N-acetyl-p-benzoquinoneimine (NAPQI), which is immediately conjugated with glutathione and subsequently excreted as cysteine and mercapturate conjugates. Only 1e4% of a therapeutic dose of paracetamol is excreted unchanged in the urine.1 In overdose, larger amounts of paracetamol are metabolized by oxidation to NAPQI since other conjugation pathways are saturated. As a result, liver glutathione stores become depleted and the liver is unable to ‘deactivate’ the toxic metabolite NAPQI. NAPQI reacts with glutathione, thereby depleting hepatic cells of their normal defence against oxidizing damage, and once this has occurred, this potent oxidizing and arylating agent inactivates key sulfhydryl groups in certain enzymes (particularly those controlling calcium homeostasis).
Management D Nicholas Bateman MD FRCP FRCPE FBPhS FAACT FEAPCCT is Honorary Professor in Clinical Toxicology at the University of Edinburgh. Formerly he was Consultant Physician and Director of the National Poisons Information Service (Edinburgh Unit) at the Royal Infirmary, Edinburgh, UK. Competing interests: none declared.
Acetylcysteine acts by replenishing cellular glutathione stores and can also repair oxidation damage caused by NAPQI, either directly or, more probably, through the generation of cysteine and/or glutathione. Acetylcysteine must be administered within 8e10 hours of ingestion if hepatic damage is to be minimized or prevented.4,9,10 A variety of treatment nomograms have been used internationally. These all commence with a paracetamol concentration
Allister Vale MD FRCP FRCPE FRCPG FFOM FAACT FBTS FBPhS FEAPCCT is Director of the National Poisons Information Service (Birmingham Unit) at City Hospital, Birmingham, and Honorary Professor, University of Birmingham, UK. Competing interests: none declared.
MEDICINE 44:3
190
Ó 2016 Published by Elsevier Ltd.
SPECIFIC SUBSTANCES
intravenous regimen, followed by continued administration of the 16-hour infusion until recovery or death. Liver transplantation has been performed successfully in patients with paracetamol-induced fulminant hepatic failure.
1.6
240 200 line 150 line 100 line
220 200 180 160
1.4 1.2 1.0
140 0.8
120 100
0.6
80 0.4
60 40
0.2
20 0 0
2
4
6
8
0.0 10 12 14 16 18 20 22 24 Time (hours)
Plasma paracetamol concentration (mmol/litre)
Plasma paracetamol concentration (mg/litre)
Nomogram for treatment of paracetamol poisoning
Intravenous paracetamol The paracetamol treatment nomogram cannot be directly applied when managing such cases.15 Although data are limited, in the UK it is suggested that acetylcysteine should be given if >60 mg/ kg paracetamol has been administered as a single intravenous dose, while others use a higher threshold.16 Pregnancy There are limited data on fetal outcome following paracetamol overdose during pregnancy. However, the information available does not suggest an increased risk of congenital malformations or fetal loss in the absence of severe maternal toxicity. Maternal treatment of paracetamol overdose should be as for the nonpregnant patient, and the antidote dose should be calculated using the patient’s actual pregnant weight up to a maximum of 110 kilograms.
Although these lines are often extended from 15 to 24 hours (dotted lines), the concentrations are not based on clinical trial data.
Reactions to acetylcysteine Adverse effects, notably nausea and vomiting and anaphylactoid reactions (rash and bronchospasm), are well recognized and occur in over 20% of patients receiving acetylcysteine.17 These reactions result in frequent treatment interruptions, patients refusing subsequent therapy and, occasionally, doctors not treating patients in the mistaken opinion that these reactions are based on an immunological, rather than a pharmacological, mechanism.3 Antihistamines and bronchodilators may be required. An approximate five times greater incidence of anaphylactoid responses in patients with paracetamol concentrations 100 mg/litre compared with that in patients with paracetamol concentrations >100 mg/litre has been reported.12 These reactions are seldom serious, but infusion of acetylcysteine should be discontinued for 30e60 minutes. A new 12-hour regimen for acetylcysteine administration reduces the incidence of these effects.18
Figure 1
taken at least 4 hours after ingestion, decline with a half-life of 4 hours, and start from 200 mg/litre, 150 mg/litre or 100 mg/litre at 4 hours (called the ‘200’, ‘150’ or ‘100’ nomogram lines) (Figure 1). It should be noted that the treatment lines are uncertain if the patient presents 15 hours or more after ingestion, or has taken a modified-release preparation of paracetamol. In 2012 the UK Medicines and Healthcare products Regulatory Agency stipulated a change in management from the 200 mg/litre line to the 100 mg/litre nomogram for all UK patients,11 a change that has been calculated to have cost the National Health Service in excess of £17 million to save one life every 2 years.12 In some countries, notably Australia and North America, the 150 mg/litre nomogram line is used. The recommended intravenous regimen is shown in Table 1 and the protocol for treating patients in Table 2. For a patient weighing >110 kilograms, the acetylcysteine dose should be calculated using a maximum of 110 kilograms, rather than the patient’s actual weight. In patients who present >24 hours after an overdose of paracetamol, morbidity and mortality are greater,13 and treatment is aimed at preventing or supporting hepatic and/or renal failure, although use of an extended course of acetylcysteine has been recommended. In a controlled trial in patients with fulminant hepatic failure, this regimen was found to reduce morbidity and mortality.14 It involves the administration of the 21-hour
Prognostic factors The overall mortality from paracetamol poisoning in untreated patients is about 5%. A prothrombin time of >20 seconds (INR >1.3), in the presence of a rise in ALT, at 24 hours after ingestion indicates that significant hepatic damage has been sustained, and a peak prothrombin time of >180 seconds is associated with survival of less than 8%.19 Systemic acidosis developing >24 hours after overdose indicates a poor prognosis; survival is only 15% in patients with blood pH of <7.3 at this time.19 Increased serum creatinine concentration is also associated with poor survival (23% in patients with serum creatinine >300 micromol/litre).19 A
Dosing regimen for acetylcysteine REFERENCES 1 Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. Br J Clin Pharmacol 1980; 10: 291Se8.
Acetylcysteine (intravenous 21.00-hour regimen) 150 mg/kg over 60 minutes, then 50 mg/kg over the next 4 hours and 100 mg/kg over the next 16 hours Total dose, 300 mg/kg over 21.00 hours Table 1
MEDICINE 44:3
191
Ó 2016 Published by Elsevier Ltd.
SPECIFIC SUBSTANCES
Management Initial investigations in all cases: plasma paracetamol, creatinine, urea and electrolytes, ALT activity, INR and full blood count Presenting £8 hours after single ingestion (taken over 1 hour) Estimate plasma paracetamol concentration as soon as 4 hours or more have elapsed. Assess the need for acetylcysteine and commence if indicated If the plasma paracetamol concentration is not available within 8 hours of the overdose, and if >150 mg/kg paracetamol has been ingested, acetylcysteine should be started but stopped if the result subsequently indicates that treatment is not required Check INR, plasma creatinine and ALT activity on completion of treatment Presenting 8e24 hours after single ingestion (taken over 1 hour) Urgent treatment is required because the efficacy of acetylcysteine declines progressively from 8 hours after overdose. If >150 mg/kg paracetamol has been ingested, start treatment with acetylcysteine immediately. Discontinue acetylcysteine only if the plasma paracetamol concentration is below the relevant treatment line (Figure 1) Repeated (staggered) overdoses (taken over 1 hour) Treatment with acetylcysteine should be given to all such patients. Hepatotoxicity is unlikely if, 24 hours or longer after the last paracetamol dose, the patient is asymptomatic, the INR is 1.3 and the plasma creatinine and ALT activity are normal Therapeutic excess (more than a licensed dose for that individual and ‡75 mg/kg in any 24-hour period) Patients ingesting 150 mg/kg or more in any 24-hour period should be treated with acetylcysteine. For patients who have taken between 75 and 150 mg/kg in any 24-hour period, discuss with a poisons information service On completion of treatment: Check INR, plasma creatinine and ALT activity. If any test is abnormal or the patient is symptomatic, further monitoring is required and expert advice should be sought Table 2
12 Bateman DN, Carroll R, Pettie J, et al. Effect of the UK’s revised paracetamol poisoning management guidelines on admissions, adverse reactions, and costs of treatment. Br J Clin Pharmacol 2014; 78: 610e8. 13 Wong A, Sivilotti MLA, Dargan PI, et al. External validation of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity from paracetamol overdose. Clin Toxicol 2015; 53: 807e14. 14 Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. Br Med J 1991; 303: 1026e8. 15 Gray T, Hoffman RS, Bateman DN. Intravenous paracetamol d an international perspective of toxicity. Clin Toxicol 2011; 49: 150e2. 16 Dart RC, Rumack BH. Intravenous acetaminophen in the United States: iatrogenic dosing errors. Pediatrics 2012; 129: 349e53. 17 Bateman DN. Paracetamol poisoning: beyond the nomogram. Br J Clin Pharmacol 2015; 80: 45e50. 18 Bateman DN, Dear JW, Thanacoody HKR, et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. Lancet 2014; 383: 697e704. 19 O’Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97: 439e45.
2 Bessems JGM, Vermeulen NPE. Paracetamol (acetaminophen)induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol 2001; 31: 55e138. 3 Ferner RE, Dear JW, Bateman DN. Management of paracetamol poisoning. Br Med J 2011; 342: d2218. 4 Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poisoning. Lancet 1995; 346: 547e52. 5 Green TJ, Sivilotti ML, Langmann C, et al. When do the aminotransferases rise after acute acetaminophen overdose? Clin Toxicol 2010; 48: 787e92. 6 Jones AF, Harvey JM, Vale JA. Hypophosphataemia and phosphaturia in paracetamol poisoning. Lancet 1989; 2: 608e9. 7 Pakravan N, Bateman DN, Goddard J. Effect of acute paracetamol overdose on changes in serum and urine electrolytes. Br J Clin Pharmacol 2007; 64: 824e32. 8 Pakravan N, Simpson KJ, Waring WS, et al. Renal injury at first presentation as a predictor for poor outcome in severe paracetamol poisoning referred to a liver transplant unit. Eur J Clin Pharmacol 2009; 65: 163e8. 9 Prescott L. Oral or intravenous N-acetylcysteine for acetaminophen poisoning? Ann Emerg Med 2005; 45: 409e13. 10 Kerr F, Dawson A, Whyte IM, et al. The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine. Ann Emerg Med 2005; 45: 402e8. 11 Medicines and Healthcare products Regulatory Agency. Benefit risk profile of acetylcysteine in the management of paracetamol overdose. 2012. London: MHRA, 2015.
MEDICINE 44:3
192
Ó 2016 Published by Elsevier Ltd.
Prostaglandin endoperoxide synthase, N-deacetylase and P450-dependent mixed-function oxidases are involved in paracetamol-induced renal damage.2
Paracetamol (acetaminophen)
Prediction of liver damage D Nicholas Bateman
The severity of paracetamol poisoning is dose-related. If a patient has ingested <150 mg/kg it is unlikely that serious toxicity will occur, whereas if a patient has ingested >150 mg/kg, the overdose is potentially serious. If the patient has risk factors such as malnutrition, acute starvation or chronic ethanol ingestion and is receiving enzyme-inducing drugs, toxicity is more likely.3 However, a single measurement of the plasma paracetamol concentration >4 hours after ingestion is a more accurate predictor of liver damage than dose alone. For example, in patients in whom the concentration lies above the line drawn from 200 mg/litre at 4 hourse30 mg/litre at 15 hours, 60% are likely to sustain liver damage (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1000 IU/litre) unless acetylcysteine is given.
Allister Vale
Abstract Paracetamol poisoning is common. If untreated, liver and/or renal failure can develop. The administration of acetylcysteine within 8e10 hours of overdose will minimize or prevent hepatic damage and ensure survival irrespective of the magnitude of the ingestion. Important prognostic factors are the international normalized ratio, pH and plasma creatinine concentration.
Keywords Acetylcysteine; hepatic encephalopathy hypophosphataemia; INR; pH; plasma creatinine; renal failure
Features Introduction Following ingestion of an overdose of paracetamol, patients can develop anorexia, nausea and vomiting, or can remain asymptomatic for the first 24 hours. Liver damage is not usually detectable by routine liver function tests until at least 18 hours after ingestion of the drug, and hepatic tenderness and abdominal pain are seldom exhibited before the second day.4 Maximum liver damage, as assessed by plasma ALT or AST activity or prothrombin time (international normalized ratio (INR)), usually occurs 72e96 hours after ingestion but may be more rapid in severe cases. Hepatic failure (manifest by jaundice and encephalopathy) can then develop between the third and fifth days; the rate of clinical deterioration reflects the severity of the overdose. More usually, prolongation of prothrombin time (INR) and a marked increase in ALT/AST activity occur without development of fulminant hepatic failure. Rate of rise of ALT correlates with severity of liver injury,5 but the magnitude of the rise is not prognostic. Renal failure as a result of acute tubular necrosis develops in about 25% of patients with severe hepatic damage and in a few without evidence of serious disturbance of liver function. Hypophosphataemia6 and hypokalaemia7 can occur due to paracetamol-induced renal tubular damage. Renal failure at first presentation is associated with a 50% mortality rate.8 Other features, including hypoglycaemia, pancreatitis, gastrointestinal haemorrhage and cerebral oedema, can occur with hepatic failure from any cause and are not direct consequences of paracetamol toxicity.
Up to 40% of all admissions to hospital with self-poisoning in the UK involve paracetamol. Patients are predominantly young, and over half have taken a previous overdose. Most deaths are associated with deliberate self-poisoning and late presentation, but therapeutic misadventures can occur in both adults and children.
Mechanisms of toxicity In therapeutic doses, 60e90% of the drug is metabolized by conjugation to form paracetamol glucuronide and sulfate; 5e10% is oxidized by mixed-function oxidase enzymes (principally CYP2E1) to form highly reactive N-acetyl-p-benzoquinoneimine (NAPQI), which is immediately conjugated with glutathione and subsequently excreted as cysteine and mercapturate conjugates. Only 1e4% of a therapeutic dose of paracetamol is excreted unchanged in the urine.1 In overdose, larger amounts of paracetamol are metabolized by oxidation to NAPQI since other conjugation pathways are saturated. As a result, liver glutathione stores become depleted and the liver is unable to ‘deactivate’ the toxic metabolite NAPQI. NAPQI reacts with glutathione, thereby depleting hepatic cells of their normal defence against oxidizing damage, and once this has occurred, this potent oxidizing and arylating agent inactivates key sulfhydryl groups in certain enzymes (particularly those controlling calcium homeostasis).
Management D Nicholas Bateman MD FRCP FRCPE FBPhS FAACT FEAPCCT is Honorary Professor in Clinical Toxicology at the University of Edinburgh. Formerly he was Consultant Physician and Director of the National Poisons Information Service (Edinburgh Unit) at the Royal Infirmary, Edinburgh, UK. Competing interests: none declared.
Acetylcysteine acts by replenishing cellular glutathione stores and can also repair oxidation damage caused by NAPQI, either directly or, more probably, through the generation of cysteine and/or glutathione. Acetylcysteine must be administered within 8e10 hours of ingestion if hepatic damage is to be minimized or prevented.4,9,10 A variety of treatment nomograms have been used internationally. These all commence with a paracetamol concentration
Allister Vale MD FRCP FRCPE FRCPG FFOM FAACT FBTS FBPhS FEAPCCT is Director of the National Poisons Information Service (Birmingham Unit) at City Hospital, Birmingham, and Honorary Professor, University of Birmingham, UK. Competing interests: none declared.
MEDICINE 44:3
190
Ó 2016 Published by Elsevier Ltd.
SPECIFIC SUBSTANCES
intravenous regimen, followed by continued administration of the 16-hour infusion until recovery or death. Liver transplantation has been performed successfully in patients with paracetamol-induced fulminant hepatic failure.
1.6
240 200 line 150 line 100 line
220 200 180 160
1.4 1.2 1.0
140 0.8
120 100
0.6
80 0.4
60 40
0.2
20 0 0
2
4
6
8
0.0 10 12 14 16 18 20 22 24 Time (hours)
Plasma paracetamol concentration (mmol/litre)
Plasma paracetamol concentration (mg/litre)
Nomogram for treatment of paracetamol poisoning
Intravenous paracetamol The paracetamol treatment nomogram cannot be directly applied when managing such cases.15 Although data are limited, in the UK it is suggested that acetylcysteine should be given if >60 mg/ kg paracetamol has been administered as a single intravenous dose, while others use a higher threshold.16 Pregnancy There are limited data on fetal outcome following paracetamol overdose during pregnancy. However, the information available does not suggest an increased risk of congenital malformations or fetal loss in the absence of severe maternal toxicity. Maternal treatment of paracetamol overdose should be as for the nonpregnant patient, and the antidote dose should be calculated using the patient’s actual pregnant weight up to a maximum of 110 kilograms.
Although these lines are often extended from 15 to 24 hours (dotted lines), the concentrations are not based on clinical trial data.
Reactions to acetylcysteine Adverse effects, notably nausea and vomiting and anaphylactoid reactions (rash and bronchospasm), are well recognized and occur in over 20% of patients receiving acetylcysteine.17 These reactions result in frequent treatment interruptions, patients refusing subsequent therapy and, occasionally, doctors not treating patients in the mistaken opinion that these reactions are based on an immunological, rather than a pharmacological, mechanism.3 Antihistamines and bronchodilators may be required. An approximate five times greater incidence of anaphylactoid responses in patients with paracetamol concentrations 100 mg/litre compared with that in patients with paracetamol concentrations >100 mg/litre has been reported.12 These reactions are seldom serious, but infusion of acetylcysteine should be discontinued for 30e60 minutes. A new 12-hour regimen for acetylcysteine administration reduces the incidence of these effects.18
Figure 1
taken at least 4 hours after ingestion, decline with a half-life of 4 hours, and start from 200 mg/litre, 150 mg/litre or 100 mg/litre at 4 hours (called the ‘200’, ‘150’ or ‘100’ nomogram lines) (Figure 1). It should be noted that the treatment lines are uncertain if the patient presents 15 hours or more after ingestion, or has taken a modified-release preparation of paracetamol. In 2012 the UK Medicines and Healthcare products Regulatory Agency stipulated a change in management from the 200 mg/litre line to the 100 mg/litre nomogram for all UK patients,11 a change that has been calculated to have cost the National Health Service in excess of £17 million to save one life every 2 years.12 In some countries, notably Australia and North America, the 150 mg/litre nomogram line is used. The recommended intravenous regimen is shown in Table 1 and the protocol for treating patients in Table 2. For a patient weighing >110 kilograms, the acetylcysteine dose should be calculated using a maximum of 110 kilograms, rather than the patient’s actual weight. In patients who present >24 hours after an overdose of paracetamol, morbidity and mortality are greater,13 and treatment is aimed at preventing or supporting hepatic and/or renal failure, although use of an extended course of acetylcysteine has been recommended. In a controlled trial in patients with fulminant hepatic failure, this regimen was found to reduce morbidity and mortality.14 It involves the administration of the 21-hour
Prognostic factors The overall mortality from paracetamol poisoning in untreated patients is about 5%. A prothrombin time of >20 seconds (INR >1.3), in the presence of a rise in ALT, at 24 hours after ingestion indicates that significant hepatic damage has been sustained, and a peak prothrombin time of >180 seconds is associated with survival of less than 8%.19 Systemic acidosis developing >24 hours after overdose indicates a poor prognosis; survival is only 15% in patients with blood pH of <7.3 at this time.19 Increased serum creatinine concentration is also associated with poor survival (23% in patients with serum creatinine >300 micromol/litre).19 A
Dosing regimen for acetylcysteine REFERENCES 1 Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. Br J Clin Pharmacol 1980; 10: 291Se8.
Acetylcysteine (intravenous 21.00-hour regimen) 150 mg/kg over 60 minutes, then 50 mg/kg over the next 4 hours and 100 mg/kg over the next 16 hours Total dose, 300 mg/kg over 21.00 hours Table 1
MEDICINE 44:3
191
Ó 2016 Published by Elsevier Ltd.
SPECIFIC SUBSTANCES
Management Initial investigations in all cases: plasma paracetamol, creatinine, urea and electrolytes, ALT activity, INR and full blood count Presenting £8 hours after single ingestion (taken over 1 hour) Estimate plasma paracetamol concentration as soon as 4 hours or more have elapsed. Assess the need for acetylcysteine and commence if indicated If the plasma paracetamol concentration is not available within 8 hours of the overdose, and if >150 mg/kg paracetamol has been ingested, acetylcysteine should be started but stopped if the result subsequently indicates that treatment is not required Check INR, plasma creatinine and ALT activity on completion of treatment Presenting 8e24 hours after single ingestion (taken over 1 hour) Urgent treatment is required because the efficacy of acetylcysteine declines progressively from 8 hours after overdose. If >150 mg/kg paracetamol has been ingested, start treatment with acetylcysteine immediately. Discontinue acetylcysteine only if the plasma paracetamol concentration is below the relevant treatment line (Figure 1) Repeated (staggered) overdoses (taken over 1 hour) Treatment with acetylcysteine should be given to all such patients. Hepatotoxicity is unlikely if, 24 hours or longer after the last paracetamol dose, the patient is asymptomatic, the INR is 1.3 and the plasma creatinine and ALT activity are normal Therapeutic excess (more than a licensed dose for that individual and ‡75 mg/kg in any 24-hour period) Patients ingesting 150 mg/kg or more in any 24-hour period should be treated with acetylcysteine. For patients who have taken between 75 and 150 mg/kg in any 24-hour period, discuss with a poisons information service On completion of treatment: Check INR, plasma creatinine and ALT activity. If any test is abnormal or the patient is symptomatic, further monitoring is required and expert advice should be sought Table 2
12 Bateman DN, Carroll R, Pettie J, et al. Effect of the UK’s revised paracetamol poisoning management guidelines on admissions, adverse reactions, and costs of treatment. Br J Clin Pharmacol 2014; 78: 610e8. 13 Wong A, Sivilotti MLA, Dargan PI, et al. External validation of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity from paracetamol overdose. Clin Toxicol 2015; 53: 807e14. 14 Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. Br Med J 1991; 303: 1026e8. 15 Gray T, Hoffman RS, Bateman DN. Intravenous paracetamol d an international perspective of toxicity. Clin Toxicol 2011; 49: 150e2. 16 Dart RC, Rumack BH. Intravenous acetaminophen in the United States: iatrogenic dosing errors. Pediatrics 2012; 129: 349e53. 17 Bateman DN. Paracetamol poisoning: beyond the nomogram. Br J Clin Pharmacol 2015; 80: 45e50. 18 Bateman DN, Dear JW, Thanacoody HKR, et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. Lancet 2014; 383: 697e704. 19 O’Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97: 439e45.
2 Bessems JGM, Vermeulen NPE. Paracetamol (acetaminophen)induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol 2001; 31: 55e138. 3 Ferner RE, Dear JW, Bateman DN. Management of paracetamol poisoning. Br Med J 2011; 342: d2218. 4 Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poisoning. Lancet 1995; 346: 547e52. 5 Green TJ, Sivilotti ML, Langmann C, et al. When do the aminotransferases rise after acute acetaminophen overdose? Clin Toxicol 2010; 48: 787e92. 6 Jones AF, Harvey JM, Vale JA. Hypophosphataemia and phosphaturia in paracetamol poisoning. Lancet 1989; 2: 608e9. 7 Pakravan N, Bateman DN, Goddard J. Effect of acute paracetamol overdose on changes in serum and urine electrolytes. Br J Clin Pharmacol 2007; 64: 824e32. 8 Pakravan N, Simpson KJ, Waring WS, et al. Renal injury at first presentation as a predictor for poor outcome in severe paracetamol poisoning referred to a liver transplant unit. Eur J Clin Pharmacol 2009; 65: 163e8. 9 Prescott L. Oral or intravenous N-acetylcysteine for acetaminophen poisoning? Ann Emerg Med 2005; 45: 409e13. 10 Kerr F, Dawson A, Whyte IM, et al. The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine. Ann Emerg Med 2005; 45: 402e8. 11 Medicines and Healthcare products Regulatory Agency. Benefit risk profile of acetylcysteine in the management of paracetamol overdose. 2012. London: MHRA, 2015.
MEDICINE 44:3
192
Ó 2016 Published by Elsevier Ltd.