Division of Clinical Pharmacology

Whenever paracetamol overdose is suspected a blood sample should be collected for urgent paracetamol measurement and routine biochemistry. A thorough history and examination is paramount as other patient factors may influence the hepatotoxicity.  Treatment of acute overdose is guided by the paracetamol nomogram below ¹. For slow release preparations or drugs affecting kinetics see note below. Potential complications may be detected by other tests.
For paracetamol results added by pathology in response to raised ALT see Paracetamol study.

Nomogram (Updated May 2004) Important: see note on reporting units

Interpretation
(see note regarding slow release preparations and drug effects)

 A Data uninterpretable if sample taken within 4 hours of ingestion. Repeat collection is recommended.  Note the minimal single hepatotoxic dose of paracetamol is 7.5 g in an adult (150 mg/kg) and if there is suspicion of a large overdose then treatment with N-acetyl cysteine is recommended immediately.

 B Liver damage highly likely. Treatment with N-acetyl cysteine is recommended.

 C Liver damage possible, especially in high risk patients. These patients should be considered for treatment with N-acetylcysteine and should be reviewed by a senior clinician.

 D Severe liver damage unlikely.  If there is doubt about the timing of ingestion or the need for treatment, treat with N-acetyl cysteine.

 E Severe liver damage is still possible if large doses of paracetamol have been ingested.  These patients should be considered for treatment with N-acetylcysteine and should be reviewed by a senior clinician.

*Note: Pharmacokinetic properties may vary if paracetamol is ingested in combination with codeine or dextropropoxyphene or other drugs that can slow gastrointestinal motility.  Recent data suggest that this nomogram may not be applicable to overdoses of extended/slow release paracetamol^2,3.  Since drug levels tend to plateau rather than peak after the ingestion of sustained release preparations, any given drug level in this setting is indicative of greater drug absorption (area under the curve) than that occurring after the ingestion of immediate release preparations.  Hence measurement of paracetamol levels after an overdose of extended/slow release paracetamol may lead to an underestimation of the need for antidote therapy if the current nomogram is used.  Seek specialist advice, treatment with N-acetyl cysteine is recommended.

High Risk Patients & Factors increasing the hepatotoxicity of paracetamol^1,4

Pregnancy – Paracetamol passes readily into the fetal circulation.  There is no contraindication to the use of N-acetyl cysteine in pregnancy and a good prognosis in pregnancy depends on early treatment – however it does not appear to cross the placenta in sheep and the ability to prevent liver toxicity in the human fetus is uncertain
Alcohol consumption - Chronic alcohol abuse
Patients on microsomal inducing drugs - barbiturates, carbamazepine, rifampicin, isoniazid, omeprazole, oral contraceptives, HIV medications
Patients likely to have glutathione depletion - recent severe fasting, acute illness with prolonged vomiting or dehydration, anorexia nervosa, bulimia
Underlying hepatic impairment - viral hepatitis, alcoholic hepatitis, NASH
Other factors - HIV infection, Gilbert’s syndrome

Protocol for Treatment with N-acetyl cysteine (NAC) (Parvolex)⁵

Initial Dose:        150 mg/kg IV in 200 ml 5% dextrose over 15 minutes
Second Dose:      50 mg/kg IV 500 mL 5% dextrose over 4 hours
Followed by:        100 mg/kg IV in 1000 mL 5% dextrose over 16 hours

Total dose:           300 mg/kg in 20 hours = 300 mg/kg

Actions: Protects the liver by restoring depleted hepatic reduced glutathione or by acting as an alternate substrate for the toxic paracetamol metabolite.
Hepatic necrosis is preventable if treatment can be instituted within < 8 hours as the upper time limit has not yet been determined.  Optimal therapy occurs when the patient is treated 10 – 12 hours post ingestions.   Any presentation > 15 hours must be considered carefully before treatment.
Indications: To be used as an antidote to paracetamol poisoning.  Paracetamol levels should be assayed before commencing treatment.
Contraindications: Hypersensitivity or previous anaphylactic reaction to acetylcysteine. Parvolex is not compatible with rubber and metals.
Adverse Effects:  Rash, bronchospasm and anaphylaxis.  NOTE: anaphylactoid reactions such as rash are not uncommon (10%) and may be treated with antihistamines, steroids and slowing the rate of infusion.
Monitoring: Continuous cardiac monitoring and regular potassium levels are recommended.

Potential Complications of Paracetamol toxicity¹

Fulminant hepatic failure - assess with liver function tests
Haematological abnormalities – assess with coagulation studies, INR – note in moderate to severe paracetamol induced hepatic necrosis disseminated intravascular coagulation (DIC) may be present
Metabolic acidosis with impaired level of consiousness and hypotension - ABGs
Renal failure – acute renal failure requiring dialysis occurs in 1% of untreated cases of paracetamol overdose and may occur in patients with no clinical or biochemical evidence of hepatotocicity
Cardiomyopathy - ECG abnormalities may be noted
Pancreatitis - serum amylase
Muscle damage - rhabdomyolysis, serum CK

Reporting Units: Serum paracetamol is reported in different units from different laboratories. The SydPath Sydney Laboratory units are mg/L (use scale on left hand side of the nomogram). Other laboratories may use micromol/L (scale on right hand side of nomogram). Ensure the correct units are being used before interpreting results with the nomogram.  To convert results in umol/L to mg/L multiply result by 0.151

References

1. Prescott LF.  Paracetamol overdose.  In Paracetamol (Acetaminophen) – A Critical Bibliographic Review.  2nd Edition 2001; pp. 527 – 624.  London: Taylor & Francis Ltd.

2. Graudins A, Aaron CK, Linden CH. Overdose of extended-release acetaminophen.  N Engl J Med. 1995 Jul 20; 333(3):196.  Medline

3. Temple AR, Mrazik TJ.  More on extended-release acetaminophen.  N Engl J Med. 1995 Nov 30;333(22):1508-9.  Medline

4. Reid A, Hazell W.  Paracetamol poisoning: Which nomogram should we use?  Emergency Medicine. 2003 15, 486-96.  Medline

5. Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT.  Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine.  Lancet 1977; ii: 432-4.  Medline