Paracetamol overdose

Background

High Risk patients

Staggered overdose

NAC & methionine

Adults < 8 hours of ingestion

Children < 8 hours of ingestion

Patients who present 8 - 15 hours post ingestion

15 - 24 hours post ingestion

>24 hours post ingestion

Specialist advice on those with liver damage

Adverse reactions to NAC

Links

Background

Hepatocellular necrosis is the major toxic effect
Biochemical evidence of maximal damage may not be attained until 72 - 96 hours after ingestion
At risk dose is more than 150mg paracetamol/kg body weight or 12g or more in total
Severe liver damage is defined as a peak plasma ALT exceeding 1000 u/L.
Those who present > 12 hours post ingestion tend to be more severely poisoned and at greater risk
Acute renal tubular damage and necrosis may also occur
If there is doubt about the timing or the need for treatment - treat
Methionine is ineffective in patients who have been given oral activated charcoal.
NAC is the treatment of choice when patients are vomiting or present more than 8 hours after ingestion.

High risk patients

Regular alcohol ingestion
Other enzyme (liver microsomal oxidases) inducers
e.g.. carbamazepine, phenytoin, phenobarbitone, primidone and rifampicin)
Glutathione depletion (e.g. malnutrition and HIV)

Do not take plasma levels within 4 hours of ingeston asthey are unreliable.

But patients may give inaccurate histoties. If in doubt, treat with NAC.

Staggered overdose

Treat with NAC and admit medical or to the CDU.

Antidote doses

N-acetylcysteine (NAC) (Parvolex)

Dosage NAC IV infusion – ADULT AND CHILD > 12 yrs

Initially 150mg/kg in 200mL glucose 5% given over 15 minutes, then
50mg/kg in 500mL glucose 5% given over 4 hours, then
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 NAC IV infusion - CHILDREN (under 12 years)

CHILD 1 MONTH-5 YEARS (OR 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.

The British National Formulary, No. 26 (1993) recommends the following dosage regimens:

Acetylcysteine. Dose: by intravenous infusion, in glucose intravenous infusion 5%, initially 150 mg/kg in 200 ml over 15 minutes, followed by 50mg/kg in 500 ml over 4 hours, then 100 mg/kg in 1000 ml over 16 hours.

Methionine. Dose: by mouth, 2.5 g initially, followed by 3 further doses of 2.5 g every 4 hours.

Management of Adult patients who present within 8 hours of ingestion

Consider charcoal if more than 150 mg/kg body weight taken and presentation within 1 hour of ingestion.
Take blood for plasma paracetamol concentration at 4 hours post ingestion.
Assess whether at high risk of severe liver damage (see above)
Confirm timings of ingestion and time blood sample and risk stratify to treatment lines A or B
If in doubt treat as high risk patients
If presenting with in 4 hours of ingestion, do not start NAC immediately. Wait until 4 hours post ingestion and take P&S levels. Start NAC if level taken at 4 hours is in the appropriate treatment range.
If the paracetamol concentration result is not available within 8 hours of ingestion ( > 150 mg/kg or > 12 g in total) start NAC immediately. It can be stopped later if subsequent level well below treatment line.

Management of children (<12yo) 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. Activated charcoal may be considered if:

>150mg/kg body weight is thought to have been ingested, and
Iit can be given without difficulty and within one hour of the overdose.

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", those with anorexia nervosa; recent fasting
Those receiving enzyme-inducing drugs (e.g. carbamazepine, phenytoin, phenobarbitone, primidone, St John's Wort and rifampicin)

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

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.

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)

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.

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

Urgent action is required ( antidote efficacy drops sharply)
Give NAC immediately without waiting for the result of the plasma paracetamol concentration measurement if it is thought that more than 150 mg/kg body weight or a total of 12 g or more has been ingested.
Assess whether at high risk of severe liver damage (see above)
Take bloods for P&S levels, INR, creatinine and ALT.
Confirm timings of ingestion and time blood sample and risk stratify to treatment lines A or B
If in doubt treat as high risk patients
If the paracetamol concentration result is not available within 8 hours of ingestion ( > 150 mg/kg or > 12 g in total) start NAC immediately.
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.
At the end of NAC infusion check INR and plasma creatinine concentration.
Patients who are symptomatic or in whom the INR and/or plasma creatinine are abnormal require further monitoring.
Vitamin K should be given if the INR is increased
FFP / clotting factors are only indicated for active bleeding.

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

Start all patients on an infusion of NAC
Measure the plasma paracetamol concentration on admission
The infusion may be stopped and the patient discharged from medical care if each of the following criteria is met:
                the patient is asymptomatic,
                the INR and plasma creatinine are normal and
                the plasma paracetamol concentration is less than 10 mg/L (0.07 mmol/L) 24 hours after ingestion.
Patients in whom the INR and/or plasma creatinine are abnormal or whose plasma paracetamol concentrations exceed 10 mg/L at 24 hours after ingestion require further monitoring and contact with a hepatologist.

Management of patients who present longer than 24 hours after ingestion

All should have their INR, plasma creatinine concentration, ALT and venous pH (or hydrogen ion / bicarb concentration) determined
We recommend that they all be discussed with a poisons information centre or a specialist liver or poisons unit.

Specialist advice on those with liver disease

Patients who develop severe liver damage may merit discussion with a specialist liver unit (not necessarily a liver transplant unit). Such discussions are likely to be of greater benefit if they are held early. Patients in this category include those who have an INR greater than 3.0, an elevated plasma creatinine, evidence of acidosis or encephalopathy, hypotension (mean arterial pressure less than 60 mmHg) or pre-existing liver disease.

Adverse reactions to NAC

N-acetylcysteine adverse effects may be localised to infusion site or
Be more generalised
- Usually occur during the first 30 minutes of administration (large dose given rapidly)
- Include nausea, flushing, itching, erythematomacular rashes, urticaria, angiooedema, bronchospasm and, rarely, hypotension or hypertension
Infusion of NAC should be stopped and an antihistamine given
Once adverse effects settled, resume infusion at the lowest infusion rate (100 mg/kg over 16 hours).