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Guidelines for the management of paracetamol poisoning in Australia and New Zealand — explanation and elaboration

Frank F S Daly, John S Fountain, Lindsay Murray, Andis Graudins and Nicholas A Buckley
Med J Aust 2008; 188 (5): 296-302. || doi: 10.5694/j.1326-5377.2008.tb01625.x
Published online: 3 March 2008

Paracetamol is the most widely used over-the-counter analgesic agent in the world. It is involved in a large proportion of accidental paediatric exposures and deliberate self-poisoning cases and is the leading pharmaceutical agent responsible for calls to poisons information centres in Australia and New Zealand. Paracetamol is also the single most commonly taken drug in overdoses that lead to hospital presentation and admission.1 Hepatic failure and death are uncommon outcomes,2,3 although paracetamol remains the most important single cause of acute fulminant hepatic failure in Western countries.4

Acute deliberate self-poisoning, accidental paediatric exposure and inadvertent repeated supratherapeutic ingestions all require specific approaches to risk assessment and management. This complexity is compounded by the existence of several different treatment nomograms in Australasia. Existing recommendations do not deal with extended-release paracetamol, and previously distributed industry-generated guidelines (from GlaxoSmithKline Consumer Healthcare [GSK]) no longer reflect current clinical toxicology practice or poison centre recommendations.To rectify this problem, new consensus guidelines have been drafted by a panel of Australian and New Zealand clinical toxicologists, with the objective of supporting clinicians in poison centres, primary care and hospital practice with concise and meaningful clinical management guidelines for presentations related to paracetamol overdose. Here, we summarise the rationale for the recommendations made in the guidelines (which are available in full at http://www.toxinz.com).

General principles of paracetamol overdose management
Risk assessment

A risk assessment, in which the clinician attempts to predict the most likely clinical course and potential complications of the patient’s presentation, should occur as soon as possible in the management of all poisoned patients. The key factors to consider for paracetamol poisoning are the dose and concentration (early), clinical and laboratory features suggesting liver damage (late), and any history suggesting increased susceptibility to toxicity.

The dosing threshold at which hepatic injury occurs after supratherapeutic paracetamol ingestion appears to be subject to wide interindividual variation and depends on the dosing context (Box 1). Serum paracetamol levels should be used to assess the need for N-acetylcysteine administration in all patients with deliberate paracetamol self-poisoning, regardless of the stated dose.

Clinical or biochemical evidence of liver injury may not be apparent for up to 24 hours after acute paracetamol overdose. The best surrogate marker indicating the potential for injury is a timed serum paracetamol level plotted on a nomogram. However, the nomogram cannot be applied for repeated or staggered doses, or if the time of ingestion cannot be determined with confidence by the treating clinician.

The most important risk factor for liver damage and death after acute paracetamol ingestion is the extent of delay beyond 8 hours until treatment with N-acetylcysteine commences. Treatment within 8 hours will prevent all serious hepatic injury. However, N-acetylcysteine has frequent adverse effects, is moderately expensive and requires hospitalisation, so it is not reasonable to adminis-ter it to every patient with possible paracetamol overdose.

Rationale for a new treatment nomogram in Australia and New Zealand

Paracetamol treatment nomograms have been used for many years in Australasia. The nomogram used appears to be a local decision,6 but they are often derived from nomograms devised overseas.7,8

The Prescott nomogram was based on a cohort of patients in Ed-inburgh and extends from 1320 μmol/L (200 mg/L) at 4 hours to 200 μmol/L (30 mg/L) at 15 hours.7 The Rumack–Matthew nomogram is based on the same data, but extrapolated to 24 hours. It also uses a “treatment line” that is plotted 25% lower (1000 μmol/L [150 mg/L] at 4 hours) to comply with a United States Food and Drug Administration requirement to provide a “safety buffer” for research and clinical purposes.8

The efficacy and safety of dosing N-acetylcysteine according to the Rumack–Matthew nomogram has been demonstrated in a study of more than 11 000 patients, with no deaths among patients who were treated within 15 hours.8 In contrast, while use of the higher Prescott line has been demonstrated to be usually safe in smaller cohorts of patients,7,9 there have been occasional reports of people who were not treated because they had concentrations below the line, but who subsequently died from acute hepatic failure.10 In addition, both these nomograms use a log scale, making it difficult to plot levels accurately.7,8

Several variables (such as chronic ethanol misuse, use of enzyme-inducing drugs, prolonged fasting, and dehydration) are hypothesised to increase the risk of hepatic injury. These “risk factors” are thought to increase the metabolism of paracetamol to the toxic metabolite NAPQI via induction of mixed function oxidases, or decrease hepatocellular glutathione stores, or both. However, the relevance of these risk factors in clinical practice remains controversial, with no consensus among clinical toxicologists.11,12 Many guidelines have recommended an arbitrary further lowering of the nomogram line (ie, to 660 μmol/L [100 mg/L] at 4 hours) for patients with such risk factors.13 This introduces further complexity into clinical risk assessment. It is our experience that clinical assessment of risk factors is done in a haphazard fashion and the “high-risk” line on the nomogram is often misinterpreted, with some clinicians treating everyone above this line, and some never using it at all.6

The aim of the new treatment nomogram, shown in Box 2, is to reconcile the hypotheses and evidence regarding risk factors while using a single nomogram line to simplify decision making. The new nomogram lowers the old Australian nomogram line13 by 25%, meaning that it starts at 1000 μmol/L (150 mg/L) at 4 hours. This provides both a margin of safety for patients who may possess risk factors and a small margin of error for estimation of time of ingestion, and avoids the need for potentially confusing additional lines. This change simplifies management guidelines, remains conservative and poses minimal inherent risk for misinterpretation and error. It is also the treatment threshold with the most clinical data to support its efficacy and safety.8

Management of paracetamol overdose
Acute paracetamol exposure with known time of ingestion

Treatment with N-acetylcysteine guarantees survival if administered within 8 hours of paracetamol ingestion, and outcome is the same regardless of when treatment is given within this 8-hour window. Beyond 8–10 hours after ingestion, efficacy decreases with increasing delay to treatment.8 If a patient presents within 8 hours of ingestion, N-acetylcysteine administration may be delayed until a serum paracetamol level plotted on the nomogram confirms it is indicated (as long as treatment can still be commenced within the 8-hour window if it is required).

For patients that present within 8 hours with a known time of ingestion, risk assessment is based on the serum paracetamol level plotted on the nomogram. Supplementary investigations such as liver function tests or a coagulation profile do not refine the risk assessment, and do not provide useful baseline data or change management in this group of patients. These tests are therefore not indicated unless risk assessment for another agent requires them. Follow-up tests are not required at the conclusion of the 20-hour N-acetylcysteine infusion, before discharge or at subsequent follow-up.

In patients who present 8 or more hours after ingestion, N-acetylcysteine should be commenced immediately if the reported dose exceeds the threshold for possible toxicity (Box 1) or the patient shows clinical signs suggestive of paracetamol toxicity (nausea, vomiting, right upper quadrant pain or tenderness). Evaluation of serum paracetamol and alanine aminotransferase (ALT) levels should then be performed as soon as possible. If the serum paracetamol level is subsequently found to be below the nomogram line, N-acetylcysteine may be ceased; if above the line, it should be continued. The baseline serum ALT level assists risk assessment and provides useful baseline data if N-acetylcysteine is indicated. Similarly, if N-acetylcysteine is commenced, baseline international normalised ratio and platelet count provide additional data to inform later risk assessments (eg, for risk of death from hepatic failure).

Box 3 summarises the steps for management of acute paracetamol exposure with known time of ingestion.

Multiple or “staggered” overdoses

In this scenario, if it has been less than 8 hours since the first dose, the patient can safely be treated as per the 1–8 hours scenario in Box 3. The rationale for this is that due to the rapid absorption of paracetamol, any later doses will only lead to overestimation of the risk. However, if it has been more than 8 hours since the first dose, treat the patient as per the > 8 hours scenario in Box 3.

Repeated supratherapeutic ingestion

There is little evidence to guide risk assessment for repeated ingestion of high doses of paracetamol. The margin of safety has for many years been assumed to be high;16 however, recent data suggest that minor subclinical elevations of serum aminotransferase levels may be quite common with prolonged therapy.17 Conversely, studies of “high-risk” patients who have taken supratherapeutic doses over 3–4 days have suggested significant hepatotoxicity is uncommon.18 Therefore, the threshold for the reported dose that causes toxicity has been made deliberately and conservatively low (see Box 1 and Box 4). However, there is evidence that the combination of a low paracetamol level and normal alanine and aspartate aminotransferase levels at any time indicates there is no risk of subsequent hepatotoxicity.10 In most cases, this rule precludes the need for prolonged treatment in this group.

Recommended investigations

Box 5 gives a summary of recommended tests and when they should be administered. For ease of reference, these are presented according to the time from ingestion to administration of N-acetylcysteine.

N-acetylcysteine

N-acetylcysteine is an effective antidote and should be administered to all patients judged to be at risk of developing hepatotoxicity after paracetamol overdose. With N-acetylcysteine therapy, morbidity from overdose can be minimised. Cysteamine and methionine have also been used to prevent hepatotoxicity, but are associated with more adverse effects than N-acetylcysteine. Methionine is also less effective, particularly in patients presenting > 8 hours post-ingestion.

Anaphylactoid reactions manifested by rash, wheeze or mild hypotension occur in 10%–50% of patients during the first two N- acetylcysteine infusions.1,8 Management is supportive, with temporary halting or slowing of the infusion, and administration of antihistamines.19 The occurrence of an anaphylactoid reaction does not preclude the use of N-acetylcysteine on another occasion if indicated. Severe life-threatening reactions are very rare, but may occur in predisposed individuals, such as patients with asthma.

N-acetylcysteine reduces mortality if commenced late in patients with established paracetamol-induced fulminant hepatic failure, although mechanisms of action in this later period may be different. In this setting, N-acetylcysteine reduces inotrope requirements, decreases cerebral oedema and increases the rate of survival by about 30%.20

New recommendations on dose calculations for N-acetylcysteine

When risk assessment indicates that N-acetylcysteine is required, it is administered as a three-stage infusion (Box 6). Each stage contains different doses, totalling 300 mg/kg over 20–21 hours.7 If hepatic injury is suspected after the three infusion stages, N-acetylcysteine is continued at the rate of the last infusion stage (100 mg/kg each 16 hours or 150 mg/kg/24 hours) until there is clinical and biochemical evidence of improvement.

N-acetylcysteine is packaged for intravenous infusion in 10 mL ampoules, each containing 2000 mg (20%). Prescription of N-acetylcysteine requires a two-stage calculation to compute the appropriate weight-based dose and then the volume required. Calculation or transcription errors may lead to potentially fatal dosing errors.21 It is recommended that dosing tables providing the required volume of 20% N-acetylcysteine by weight categories be used to chart the volume required in each infusion. This precludes the need for calculations and decreases the potential for error. Such tables are found in the N-acetylcysteine product information and have also been reproduced in the new guidelines (Box 7).

Calculation of N-acetylcysteine doses is based on estimated lean bodyweight to the nearest 10 kg. A formula is provided to calculate N-acetylcysteine volume in each infusion for patients weighing more than 90 kg. For children, the dose of N-acetylcysteine is calculated in the same way, but with the volume reduced appropriately (Box 8).

Subsequent management of hepatotoxicity and liver failure

Only a small proportion of patients who present late develop severe hepatotoxicity and fulminant hepatic failure.1,8 This complex subject was considered beyond the scope of the new guidelines. Clinicians should consult a specialist liver unit for advice on the management of patients with liver failure or signs that indicate a poor prognosis.22-24

  • Frank F S Daly1,2,3
  • John S Fountain4
  • Lindsay Murray5
  • Andis Graudins6,3
  • Nicholas A Buckley3,7

  • 1 Emergency Medicine, Royal Perth Hospital, Perth, WA.
  • 2 University of Western Australia, Perth, WA.
  • 3 NSW Poisons Information Centre, The Children’s Hospital at Westmead, Sydney, NSW.
  • 4 National Poisons Centre, University of Otago, Dunedin, New Zealand.
  • 5 Emergency Medicine, Sir Charles Gairdner Hospital, Perth, WA.
  • 6 Emergency Medicine, Prince of Wales Hospital, Sydney, NSW.
  • 7 Professorial Medical Unit, Prince of Wales Hospital Clinical School, University of New South Wales, Sydney, NSW.


Correspondence: frank.daly@health.wa.gov.au

Acknowledgements: 

We would like to thank Hazel Palmer of Scius Solutions for assistance in the preparation of this manuscript; her contribution was funded by an unrestricted educational grant from GlaxoSmithKline Consumer Healthcare Australia (GSK). GSK provided funding to enable the development of the new guidelines poster only; they had no role in the preparation, review or approval of this manuscript.

Competing interests:

Frank Daly, John Fountain and Lindsay Murray each received a small honorarium from GSK for attending a half-day round-table meeting to discuss the content and scope of the poster (“Guidelines for the management of paracetamol overdose”) upon which this article is based.

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