Synonyms: acetaminophen poisoning

Background

• It is important to remember that, when used at therapeutic levels, paracetamol is safe and effective.
• Paracetamol overdose may occur intentionally and accidentally; the latter due to the high number of combination products available over-the-counter.

Toxicity

• Paracetamol can cause serious or fatal adverse effects at around 150 mg/kg for most adults.
• The level is higher for young children. NB: Toxbase® says there is no choice but to treat children younger than 6 years the same as adults. However, there is a large body of data in the published literature that shows the threshold for likely hepatotoxicity exceeds 225 mg/kg for this age group and so using a value of 200 mg/kg is a safe option and reduces waiting times and the number of unnecessary blood tests with their associated distress.⁴
• There is a theoretical argument for increased risk with enzyme induction or low glutathione reserves. There are case reports of chronic alcoholics taking relatively small overdose (OD) or even therapeutic doses of paracetamol who develop liver failure. However close examination of these case reports shows up some inconsistencies and suggests that it is unclear that these all provide any substantial evidence supporting the hypothesis. Even the seminal paper that formed the basis of the UK guidelines suggests that there is no evidence base for the practice of a 50% high-risk line on the nomogram.⁴

Pathophysiology

After taken orally, paracetamol is well absorbed from the stomach and small intestine and reaches a peak plasma concentration in one hour.
It is inactivated by the liver by conjugation leading to two metabolites; glucoronide or sulfate. It is then renally excreted through urine.

• When taken in overdose the liver conjugation becomes inundated, causing paracetamol to be metabolised by an alternative pathway.
• This results in a toxic metabolite, N-acetyl-p-benzoquinone imine (NABQI), which is itself inactivated by glutathione, rapidly preventing any harm.
• However, glutathione can be run down with minor increases in the toxin and, when this occurs, NABQI reacts with nucleophilic aspects of the cell, leading to necrosis. Necrosis occurs in the liver and in the kidney tubules.

Toxicity is increased in patients with induction of the P450 system through drugs such as rifampicin, phenobarbital, isoniazid, phenytoin, carbamazepine and alcohol.
This also occurs in patients with low glutathione reserves, as a product of:

• Genetic variation
• HIV positive
• Malnutrition
• Alcohol-related or other liver disease

Paediatric patients (under the age of 5 years) seem to fare better after paracetamol poisoning, perhaps due to a greater capacity to conjugate with sulfate, enhanced detoxification of NABQI or greater glutathione stores. However, it should not be assumed that treatment in children should be different than for adults, since no controlled studies have supported any alternative paediatric therapy.

Clinical features

• Commonly, patients are asymptomatic for the first 24 hours or have non-specific abdominal symptoms (such as nausea and vomiting).
• Hepatic necrosis begins to develop after 24 hours (elevated transaminases, RUQ pain and jaundice) and can progress to acute liver failure.
• Patients may also develop:
  • Encephalopathy
  • Oliguria
  • Hypoglycaemia
  • Renal failure - usually occurs around day 3
  • Lactic acidosis

Assessment

History

• Number of tablets, formulation, any concomitant tablets (include herbal remedies as substances, such as St John's wort - an enzyme inducer)
• Time of overdose
• Suicide risk - was a note left?

Examination

• Usually very little to find, until the patient develops ALF
• If ALF develops, may see jaundice, hepatic flap, encephalopathy and tender hepatomegaly

Investigations

• Paracetamol level (usually performed with a salicylate level); take paracetamol level 4 hours post ingestion, or as soon as patient arrives if:
  • Time of overdose >4 hours
  • Staggered overdose (in staggered overdoses, level not interpretable except to confirm ingestion)
• U&E, creatinine - to look for renal failure and have a baseline
• Liver function tests: ALT >1000 IU/L indicates severe liver damage
• Glucose: hypoglycaemia is common in hepatic necrosis and capillary blood glucose should be checked hourly
• Clotting screen: prothrombin time is the best indicator of severity of liver failure and the INR should be checked 12-hourly
• FBC
• Arterial blood gas; acidosis can occur at a very early stage, even when the patient is asymptomatic. It is seen in up to 10% of patients with ALF.

Management

Management if ≤8 hours after ingestion adults and children aged 6 years and over⁵

• Consider administration of activated charcoal (charcoal dose: 50 g for adults) if more than 150 mg/kg or 12 g paracetamol (whichever is the smaller) in total has been taken within 1 hour. If the patient has risk factors (see below) consider treatment at a lower dose (75 mg/kg). Note that for obese patients (>110 kg), the toxic dose in mg/kg should be calculated using 110 kg, rather than their actual weight.
• More recently the indications for single dose activated charcoal in children (1 g/kg body weight) are increasingly recognised as being more limited.⁴ Use should be restricted to situations where:
  • The toxin remains in the gastrointestinal tract (<1hr for most agents).
  • The potential benefits (prevention of serious toxicity/death not treatable by other means) outweigh the potential risks (vomiting, aspiration - particularly where there is a risk of reduced consciousness or seizures, corneal abrasions, impaired absorption of other antidotes).
  It should not be used punitively. NB: with paracetamol elixir overdoses in young children:
  • Absorption is usually complete in ≤30 minutes, before charcoal can be administered.
  • The OD is nearly always accidental and there are no reports of death in such cases in children ≤8yrs.
  • Charcoal is not life-saving.
  • Children's co-operation of drinking the unpalatable charcoal is often low (with increased vomiting risk), and the narrow bore of paediatric tubes are troublesome for the nasogastric route.
  In older, co-operative children and adults, charcoal may be offered if <1hr from ingestion of a deliberate OD or accidental OD >150 mg/kg in the hope it might reduce the 4-hour paracetamol level and make N-acetylcysteine (NAC) unnecessary.
• Wait until 4 hours from ingestion have elapsed then take a venous blood sample for urgent measurement of the plasma paracetamol concentration. Plasma concentrations measured less than 4 hours after ingestion cannot be interpreted. Measure U&Es, creatinine, LFTs and INR. NB: history is not always reliable. If in any doubt on dosage, check a 4-hour concentration. Toxbase® suggests frequent repeated blood tests - but in practice, if NAC treatment is started early and the initial tests are normal, then the number of tests can be reduced.
• Assess the risk of severe liver damage from the plasma paracetamol concentration/time from ingestion graph which follows. High-risk patients may be malnourished, have nutritional deficiency and/or chronic debilitating illness, or hepatic enzyme induction, or evidence of ongoing liver injury.

We thank Dr Alan Hutchings for permission to reproduce this graph.

Management of all patients presenting 8 to 24 hours after ingestion

• Give NAC immediately if it is thought that more than 150 mg/kg body weight or 12 g in an adult (whichever is the smaller) has been ingested. If the patient has risk factors (see below) consider treatment at a lower dose (75 mg/kg). Note that for obese patients (>110 kg) the toxic dose in mg/kg should be calculated using 110 kg, rather than their actual weight.
  
  DO NOT WAIT for the result of the plasma paracetamol concentration. The efficacy of the antidote declines rapidly during this period and it must therefore be given urgently.
  
  
• Take blood for urgent measurement of the plasma paracetamol concentration, U&Es and creatinine, LFTs and INR.
• Assess the risk of liver damage from the plasma paracetamol/time from ingestion graph above.

If the patient has taken a significant overdose (based on the history), but the initial paracetamol level is below the treatment line then repeat the level 4 hours later, as there can be delayed absorption.

Refer to ICU if fulminant liver failure - those treated with NAC to the medical team and all parasuicides to the psychiatric team.

N-acetylcysteine treatment

NAC is believed to work by a number of protective mechanisms. It acts as a precursor for glutathione, promoting normal conjugation of any remaining paracetamol, and also supplies thiols that function as antioxidants. Its protective effect is greatest when administered within 12 hours of ingestion. Therapy with NAC has been shown to decrease mortality in late-presenting patients with fulminant hepatic failure.
Treatment must be started within 8 hours of ingesting if maximum protection is to be obtained.

• <5% of patients develop an allergic reaction to NAC (rash, bronchospasm and hypotension).
• If they do then the rate of the infusion should be slowed down.
• If the patient has had previous allergic reactions to NAC then consider giving intravenous hydrocortisone and chlorphenamine prior to starting the infusion.
• An alternative is methionine;⁶ however, absorption may be unreliable if there is vomiting, or activated charcoal administration. Also methionine is less effective unless given early on. Give 2.5 g methionine po every 4 hours for 4 doses (Child <6yrs give 1g po every 4 hours for 4 hours) if within 12 hours of overdose.

Treatment usually continues for the duration once NAC is started, regardless of the plasma levels. This usually takes 24 hours.
Prior to discharge it is sensible to re-check the INR, renal tests and LFTs.
Patients should be advised to return if vomiting occurs after discharge.

Late presentation

The treatment of patients presenting more than 24 hours after ingestion is controversial. Management is detailed on Toxbase® and is similar to presentation between 8 and 24 hours after the overdose.

• Measure INR, creatinine, ALT and venous blood acid/base balance or bicarbonate.
• If any of these is abnormal discuss with your nearest National Poisons Information Centre (0870 600 6266).

Paracetamol overdose during pregnancy

Paracetamol overdose is the most common drug taken in overdose during pregnancy.⁸The resulting toxic metabolites can cross the placenta and lead to hepatocellular necrosis of maternal and fetal liver cells.

NAC can bind the toxic metabolites in the mother and fetal circulation as it crosses the placenta. NAC appears to be safe during pregnancy and therefore should be administered.

Criteria for referral to specialist unit

• Encephalopathy or raised intracranial pressure (ICP). Signs of CNS oedema include BP >160/90 (sustained) or brief rises (systolic >200 mmHg), bradycardia, decerebrate posture, extensor spasms, and poor pupil responses. ICP monitoring can help.
• INR >2.0 at or before 48 hours or >3.5 at or before 72 hours (so measure INR every 12 hours). Peak elevation occurs around 72-96 hours. LFTs are not good markers of hepatocyte death.
• Renal impairment (creatinine >200 μmol/L). Monitor urine flow. Daily U&E and serum creatinine (use haemodialysis if >400 μmol/L).
• Blood pH <7.3 (lactic acidosis results in tissue hypoxia).
• Systolic BP <80 mmHg despite adequate fluid resuscitation.
• Hypoglycaemia.
• Metabolic acidosis (pH <7.3 or bicarbonate <18 mmol/L).

Prognosis

The mortality from severe liver failure is <5% with good supportive care.

Although liver transplantation only has a limited application,⁵ patients must be identified as early as possible, preferably on the second day. Current data indicates a poor prognosis if:

• An arterial pH <7.30 (hydrogen ion concentration >50 nmol/L) on or after day 2 post overdose (found in ~70% of cases with a poor prognosis).
• A combination of a prothrombin time of more than 100 seconds (INR >6.5), plasma creatinine >300 μmol/L and grade 3 or 4 hepatic encephalopathy (only a 17% survival rate).
• An increase in prothrombin time between day 3 and day 4 after overdose.

Liver transplantation is probably contra-indicated in patients with severe hypotension, severe cerebral oedema and serious infection.

Document references

1. Fagan E, Wannan G. Reducing paracetamol overdoses. BMJ Editorial; December 1996
2. Secretary of State for Health. Saving lives: our healthier nation. London: Department of Health, 1999.
3. Bateman DN; Limiting paracetamol pack size: has it worked in the UK? Clin Toxicol (Phila). 2009 Jul;47(6):536-41. [abstract]
4. Frank F S Daly, John S Fountain, Lindsay Murray, Andis Graudins and Nicholas A Buckley. Guidelines for the management of paracetamol poisoning in Australia and New Zealand — explanation and elaboration. MJA 2008; 188 (5): 296-302
5. Toxbase; (Registration is free for doctors who are employed by an NHS practice)
6. Vale JA, Proudfoot AT; Paracetamol (acetaminophen) poisoning. Lancet. 1995 Aug 26; 346(8974):547-52.; National Poisons Information Service (Birmingham Centre), City Hospital.
7. Ward SJ; Management of paracetamol poisoning. Lancet. 1995 Nov 4; 346(8984):1236.
8. Wilkes JM, Clark LE, Herrera JL; Acetaminophen overdose in pregnancy.; South Med J. 2005 Nov;98(11):1118-22. [abstract]
9. Dargan PI, Jones AL; Acetaminophen poisoning: an update for the intensivist.; Crit Care. 2002 Apr;6(2):108-10. Epub 2002 Mar 14. [abstract]

Internet and further reading

• Defendi GL, Tucker J; Toxicity, Acetaminophen. eMedicine, December 2008.
• Kingston PCT; Drug overdose/Acute poisoning.

Acknowledgements