Paracetamol Information Centre - Guidelines for the Management of Acute Paracetamol Overdosage

These guidelines were devised for use in the UK. Conditions and practices may vary outside the UK, for example availability and rapidity of laboratory test results, or availability and use of antidote medication or the presence of variations of paracetamol preparations not available in the UK. Therefore these guidelines may not be appropriate for countries outside the UK and Ireland.

Please note, in the USA paracetamol is known as acetaminophen.

Important Information

Those managing patients with acute paracetamol overdosage should be aware that:

1 These guidelines can only give guidance, cannot cover every eventuality and clinical judgement should always prevail. Patients can be unreliable at recalling the time of an overdose and the number of tablets taken. Some will have taken only paracetamol, some will have taken combination tablets containing paracetamol and other ingredients such as codeine or dextropropoxyphene, while others will have taken several different types of tablets, including those containing paracetamol. Some may have taken several different preparations that all contain paracetamol, and history is therefore only an indication of dose. If in ANY doubt check a 4 hour blood paracetamol concentration (see 4 below). These guidelines are intended solely for the management of the paracetamol element of an overdose. Details of any other substances taken must be obtained and treated appropriately.

2 Hepatocellular necrosis is the major toxic effect of paracetamol poisoning. Biochemical evidence of maximal damage may not be attained until 72-96 hours after ingestion of the overdose. Severe liver damage in the context of paracetamol poisoning has been defined as a peak plasma alanine aminotransferase (ALT) activity exceeding 1000 iu/L. Most patients who are clinically unwell have peak ALT activities of several thousand units per litre. For those who do not have ready access to ALTs, aspartate transaminase (AST) may be substituted throughout these guidelines. An AST exceeding 1000 iu/L indicates severe liver damage. In clinical practice a more accurate test for assessing prognosis is the prothrombin time (INR). Acute renal tubular damage and necrosis may occur, usually in association with hepatocellular necrosis, but rarely in the absence of major liver damage.

3 Any patient should be considered at risk of severe liver damage if he/she has ingested more than 150mg paracetamol/kg body weight, or, in adults, more than 12g (24 standard tablets), whichever is the smaller.

4 Early assessment of the risk of liver damage requires urgent measurement of the patient's plasma paracetamol concentration and blood should be taken for this purpose as soon as possible after 4 hours or more have elapsed since the overdose. Plasma concentrations taken within 4 hours should not be requested as they cannot reliably be interpreted because of the possibility of continuing absorption and distribution of the drug.

5 The time interval since ingestion is critical in assessing whether treatment is required but is often difficult to establish. Detailed questioning of the patient and others is necessary.
Patients sometimes give inaccurate histories. If there is doubt about the timing or the need for treatment, treat.

6 The treatment lines on the accompanying graph are estimates of risk based on the best available clinical evidence. They are critically dependent upon the accuracy of the history with respect to the time of overdose ingestion. Beyond 15 hours, the risk estimates are less reliable and clinical judgement becomes more important in management.

7 Staggered overdose. In patients who have taken several overdoses of paracetamol over a short period of time, the plasma paracetamol concentration will be more difficult to interpret as the treatment graph relates to a single acute ingestion. Such patients should be considered as at serious risk and considered for treatment with N-acetylcysteine (NAC). They can be discharged after NAC treatment or 24 hours from the last paracetamol dose provided they are asymptomatic and the International Normalised Ratio (INR), plasma creatinine and ALT are normal.

8 Enhanced risk. Patients who regularly consume alcohol in excess of currently recommended limits (particularly those who are malnourished), those who regularly take enzyme-inducing drugs (e.g. carbamazepine, phenytoin, phenobarbitone, primidone, St John's Wort and rifampicin) and those with conditions causing glutathione depletion (e.g. malnutrition, eating disorders, malabsorption states and HIV infection) may be at risk of liver damage from lower plasma paracetamol concentrations than others. The plasma paracetamol concentration for such patients should be considered in relation to treatment line B on the graph.

9 Patients who present 15 hours or longer after ingestion are more difficult to treat successfully with an antidote and are at greater risk of developing serious liver damage. Measures to assist in determining the prognosis include the INR, plasma bicarbonate, venous blood acid/base balance, plasma creatinine and liver function tests.

10 All patients taking a deliberate paracetamol overdose should be considered for social and/or psychological assessment prior to discharge.

11 For further advice for hospital staff in the UK & Ireland, for example on staggered overdoses, severe liver damage, persisting abnormalities of liver function, adverse reactions to NAC or any concerns regarding management, contact the National Poisons Information Service (NPIS):

NPIS (UK) 0870 600 6266

Dublin 01 837 9964 or 01 809 2566

NPIS advice on paracetamol overdosage is also available to UK hospital departments and general practitioners on TOXBASE at http://www.TOXBASE.org

Management of ADULT patients who present within 8 hours of ingestion

1 There is little evidence that undertaking gastric lavage will be of benefit to a patient in whom paracetamol is known to have been the only substance ingested.

Though the benefit has not been demonstrated for paracetamol poisoning, administration of 50g activated charcoal may be considered if:
(a) more paracetamol than 150mg/kg body weight is thought to have been ingested, and
(b) it can be given within one hour of the overdose.

2 Take blood for urgent estimation of the plasma paracetamol concentration as soon as possible after 4 hours or more have elapsed since the time of ingestion. NOTE EARLIER PARACETAMOL CONCENTRATION MEASUREMENTS ARE CLINICALLY UNINTERPRETABLE (See Important Information 4 & 5).

3 Assess whether the patient is at enhanced risk of severe liver damage (See Important Information 8 & 9).

5 A patient need not be treated if the plasma paracetamol concentration is below the relevant line on the treatment graph.

6 Start treatment with NAC in patients whose plasma paracetamol concentration related to the time from ingestion is above the relevant line on the graph (See separate panel for NAC dosage).

7 If the plasma paracetamol concentration result is not available within 8 hours of the overdose and if more than 150mg/kg body weight or 12g (whichever is the smaller) is thought to have been taken, treatment with NAC should be started at once and stopped if the plasma paracetamol concentration subsequently indicates that it is not required.

8 When NAC is started within 8 hours of the overdose it is reasonable to expect patients to be declared fit for discharge from medical care on completion of its administration. However, the International Normalised Ratio (INR), plasma creatinine and ALT must be checked for normality on completion, or just prior to completion of the treatment and before discharge. Patients should be advised to return to hospital if vomiting or abdominal pain develop or recur. NB a useful suggestion is to take a blood sample 1 hour prior to the end of the infusion to avoid time delays without infusion.

Management of CHILDREN (<12 years) who present within 8 hours of ingestion

Paracetamol poisoning with children's liquid preparations is rarely serious. Children poisoned with adult paracetamol preparations are at a much higher risk of serious liver and renal damage.

1 There is little evidence that undertaking gastric lavage will be of benefit in a child in whom paracetamol is known to have been the only substance ingested.

Though the benefit has not been demonstrated in paracetamol poisoning administration of activated charcoal may be considered if:
(a) more paracetamol than 150mg/kg body weight is thought to have been ingested, and
(b) it can be given without difficulty and within one hour of the overdose.

2 The child should be assessed to determine whether they may be at enhanced risk of developing severe liver damage. This category includes: underweight children with 'failure to thrive' whatever the cause; those with anorexia nervosa; recent fasting; and those receiving enzyme-inducing drugs (e.g. carbamazepine, phenytoin, phenobarbitone, primidone, St John's Wort and rifampicin) (See Important Information 8 & 9).

3 Take blood for urgent estimation of the plasma paracetamol concentration as soon as possible after 4 hours or more have elapsed since the time of ingestion. NOTE EARLIER PARACETAMOL CONCENTRATION MEASUREMENTS ARE CLINICALLY UNINTERPRETABLE (See Important Information 4 & 5). If there is absolute certainty that a single dose of paracetamol of <150mg/kg body weight has been ingested, or <75mg/kg in children at enhanced risk of developing severe liver damage, this can reasonably be considered unnecessary and the child may be discharged.

4 If the plasma paracetamol concentration is above line A of the paracetamol overdose treatment graph or above line B for 'at enhanced risk' patients, treatment should be started with NAC by intravenous infusion (See separate panel for children's NAC dosage)

5 Following accidental ingestion, a child need not be admitted if the plasma paracetamol concentration is below the relevant line on the treatment graph and the history is consistent with <150mg/kg body weight paracetamol having been ingested.

6 When NAC is started within 8 hours of the overdose it is reasonable to expect the child to be declared fit for discharge from medical care on completion of its administration. However, the International Normalised Ratio (INR), plasma creatinine and ALT should be checked for normality on completion, or just prior to completion, of the treatment and before discharge. Advice should be given for the child to return to hospital if vomiting or abdominal pain develop or recur.

Management of children who present more than 8 hours after ingestion should follow the advice given for ALL patients

Management of ALL patients who present 8 - 15 hours after ingestion

1 Urgent action is required because the efficacy of NAC declines progressively from 8 hours after the overdose. Therefore, if it is thought that more than 150mg/kg body weight or in adults a total of more than 12g (whichever is the smaller) has been ingested, start NAC immediately, without waiting for the result of the plasma paracetamol concentration (See separate panel for NAC dosage).

2 In all patients take blood for an urgent estimation of the plasma paracetamol concentration and also measure the INR, plasma creatinine and ALT.

3 Assess whether the patient is at enhanced risk of severe liver damage (See Important Information 8 & 9).

5 In patients not already receiving NAC, start treatment with NAC in those whose plasma paracetamol concentration related to the time from ingestion is above the relevant line on the graph or if the INR, plasma creatinine or ALT is abnormal (See separate panel for NAC dosage).

6 In patients already receiving NAC, only discontinue NAC if the plasma paracetamol concentration is below the relevant treatment line on the graph and there is no abnormality of the INR, plasma creatinine or ALT and the patient is asymptomatic. Continue the infusion if there is any doubt as to the timing of the overdose.

7At the end, or just prior to the end of NAC infusion, a blood sample should be taken for determination of the INR, plasma creatinine and ALT. If any is abnormal or the patient is symptomatic, further monitoring is required and advice sought from TOXBASE (http://www.TOXBASE.org) or the NPIS (0870 600 6266).

8 Patients with normal INR, plasma creatinine and ALT and who are asymptomatic may be discharged from medical care. They should be advised to return to hospital if vomiting or abdominal pain develop or recur.

Management of ALL patients who present 15 - 24 hours after ingestion

1 Urgent action is required because the efficacy of NAC is limited more than 15 hours after the overdose. Therefore, start NAC immediately, without waiting for the result of the plasma paracetamol concentration, in all patients unless convinced that less than 150mg/kg body weight or in adults less than 12g has been ingested (See separate panel for NAC dosage).

2 In all patients, take blood for an urgent estimation of the plasma paracetamol concentration and determination of the INR, plasma creatinine and ALT.

3 Assess whether the patient is at enhanced risk of severe liver damage (See Important Information 8 & 9).

4 The risk of the patient developing severe liver damage should then be determined by considering the plasma paracetamol concentration related to the time from ingestion using treatment line A on the graph if the patient is not at enhanced risk and line B for others. The prognostic accuracy of these lines after 15 hours is uncertain but a plasma paracetamol concentration above the relevant treatment line should be regarded as carrying serious risk of severe liver damage.

5 At the end of the NAC infusion, a blood sample should be taken to determine the INR, plasma creatinine and ALT. If any is abnormal or the patient is symptomatic, further monitoring is required and advice sought from TOXBASE. (http://www.TOXBASE.org) or the NPIS (0870 600 6266).

6 Patients with normal INR, plasma creatinine and ALT at this time, and who are asymptomatic may be discharged from medical care. They should be advised to return to hospital if vomiting or abdominal pain develop or recur.

Management of ALL patients who present more than 24 hours after ingestion

All patients should have their INR, plasma creatinine and ALT determined and venous blood acid/base balance or bicarbonate measured. It is recommended that in the event of any abnormalities in these tests TOXBASE should be consulted, or the case discussed with the NPIS (0870 600 6266) in order to decide further action.

Treatment Lines

Chart

Click here for enlarged Treatment Lines Chart

For treatment of patients at enhanced risk see above

N-acetylcysteine (NAC) (Parvolex)

Dosage for NAC intravenous infusion – ADULT AND CHILD OVER 12 YEARS

(1) Initially 150mg/kg in 200mL glucose 5% given over 15 minutes, then
(2) 50mg/kg in 500mL glucose 5% given over 4 hours, then
(3) 100mg/kg in 1000mL glucose 5% given over 16 hours

NPIS advises that for very obese patients (over 110kg) the toxic dose of paracetamol in mg/kg should be calculated using a maximum of 110kg, rather than the patient’s actual weight. Similarly the antidote dose should also be based on a maximum of 110kg for this very obese group.

Dosage for NAC intravenous infusion - CHILDREN (under 12 years)
(From BNF for Children 2006, please consult for full details of administration. Please note BNFC is updated annually each July.)

CHILD 1 MONTH-5 YEARS (OR BODY WEIGHT UNDER 20 KG)
(1) Initially 150mg/kg in 3 mL/kg glucose 5% given over 15 minutes, followed by
(2) 50mg/kg in 7 mL/kg glucose 5% given over 4 hours, then
(3) 100mg/kg in 14 mL/kg glucose 5% given over 16 hours

CHILD 5-12 YEARS (OR BODY WEIGHT OVER 20 KG)
(1) Initially 150mg/kg in 100 mL glucose 5% given over 15 minutes, followed by
(2) 50mg/kg in 250 mL glucose 5% given over 4 hours, then
(3) 100mg/kg in 500 mL glucose 5% given over 16 hours

Note: If for any reason glucose (dextrose) is unsuitable, 0.9% sodium chloride solution may be substituted.

Adverse reactions to NAC and their management

NAC may cause adverse effects which may be localised to the area surrounding the infusion site or may be more generalised. These usually occur during the first 30 minutes of administration when large amounts of NAC are being given rapidly. They include nausea, flushing, itching, erythematous rash, urticaria, angioedema, bronchospasm and, rarely, hypotension or hypertension. Infusion of NAC should be stopped and, if necessary, an intravenous antihistamine given. Once any adverse effects have settled, the infusion regimen can usually be resumed without problems at the infusion rate of 50mg/kg over 4 hours.

(NPIS advice on paracetamol overdosage is also available to UK hospital departments and general practitioners on TOXBASE at http://www.TOXBASE.org)

These NPIS guidelines are produced and distributed by the Paracetamol Information Centre. Revised edition 2007.

Highlands Barn,
Hardwick Road,
Starston,
Harleston,
Norfolk IP20 9PJ

Tel: 01379 852983
Fax: 01379 852135
Email: gbrandon@btinternet.com
Website: http://www.pharmweb.net/paracetamol.html