Question from practice: Management of paracetamol overdose
Q: I started taking paracetamol tablets for my flu and then my partner bought me some Lemsip sachets. So I took both late last night, this morning and just before lunch before I realised I shouldn’t have because the sachets have paracetamol too. Do I need to go to the hospital? I feel ok, apart from my flu.
A. Paracetamol poisoning is the most common form of poisoning in the UK.1 In 2012–13, the National Poisons Information Service (NPIS) received 6,951 telephone enquiries relating to paracetamol overdose and its online information for paracetamol was accessed over 100,000 times.1
Deliberate overdose with paracetamol is a common method of self-harm — from 2000 to 2008, between 90 and 155 deaths each year in the UK were caused by poisoning with paracetamol alone.2 This is particularly true for young people, with one British study reporting that, of children aged under 15 years presenting to hospital after deliberate overdose, more than 50 per cent had taken paracetamol.3
Why is overdose dangerous?
Paracetamol itself is not hepatotoxic. However, a metabolite of paracetamol, N-acetyl-p-benzoquinone-imine (NAPQI), can cause hepatocyte necrosis.4 Most elimination of paracetamol occurs via the liver, with only 1–4 per cent of a therapeutic dose excreted unchanged in the urine. The primary metabolic pathways for paracetamol are glucuronidation and sulfation. Both produce non-toxic metabolites.4
A small proportion of paracetamol is metabolised via cytochrome P450 isoenzymes (mostly CYP 2E1 but also CYP 3A4) to produce NAPQI. At therapeutic doses of paracetamol NAPQI is rapidly converted by glutathione to cysteine and mercapturic acid conjugates, both of which are non-toxic. However, when the concentration of NAPQI exceeds that of intracellular glutathione, NAPQI is able to bind to hepatocytes and cause necrosis.4
Hepatic necrosis caused by NAPQI can lead to fulminant liver failure (which may require liver transplantation) and death.
Is there an antidote?
Acetylcysteine prevents NAPQI-induced hepatic necrosis.
It is considered to be 100 per cent effective in preventing liver damage and death if it is administered within eight hours of overdose,4 after which the efficacy declines rapidly. Although it is most effective if treatment is started within eight hours of paracetamol ingestion, acetylcysteine protects the liver if infused up to, and possibly beyond, 24 hours of ingestion.5
It is thought that acetylcysteine prevents hepatic necrosis by increasing synthesis of glutathione. Other mechanisms that may contribute to the protective effect of acetylcysteine include improved haemodynamics and oxygen use, increased hepatic clearance, and decreased cerebral oedema.4, 5 The antioxidant effect of acetylcysteine may be protective in the later stages of paracetamol overdose.4
How much is too much?
Hepatotoxicity can occur after ingestion of more than 150mg/kg paracetamol within 24 hours.5,6 Rarely, hepatotoxicity can develop after ingestion of doses as low as 75mg/kg within 24 hours.5,6
However, for obese patients, it is important that potentially toxic doses of paracetamol are not underestimated, and when calculating the total amount of paracetamol ingested in mg/kg for a patient who weighs more than 110kg, 110kg should be used, rather than actual body weight.6 For pregnant women, calculations should be made using the woman’s pre-pregnancy weight.6
All patients ingesting paracetamol in the context of self-harm should be referred to hospital for assessment irrespective of reported dose.6
Who needs treatment with acetylcysteine?
In the hours following ingestion of a possibly toxic dose of paracetamol, it is difficult to use clinical signs to predict which patients require treatment because hepatic damage develops over one or two days, and is generally maximal three to four days after overdose.4 However, assessing the risk of toxicity at this stage is critical because treatment with acetylcysteine is most effective if given in the first eight hours after ingestion.4
To help clinicians make decisions around whether or not a patient requires treatment, patients presenting with reported paracetamol overdose can be categorised according to pattern and timing of ingestion and circumstances as follows:
- Acute overdose with known time of ingestion
- Overdose with uncertain time of ingestion
- Staggered overdose
- Therapeutic excess
If there is any uncertainty about a patient’s risk of toxicity after a paracetamol overdose, treatment with acetylcysteine should be started.6 The Panel details treatment and next steps.
Giving acetylcysteine and steps after treatment
The total dose of acetylcysteine recommended for the management of paracetamol toxicity is 300mg/kg; this dose should be divided into three consecutive intravenous infusions, which are given over a total of 21 hours as follows:5,7
- First infusion — 150mg/kg given as an intravenous infusion over one hour
- Second infusion — 50mg/kg given as an intravenous infusion over four hours
- Third infusion — 100mg/kg given as an intravenous infusion over 16 hours
Simplified dosing tables, which include infusion volumes, are provided in the British National Formulary and in the summaries of product characteristics for acetylcysteine products.
For any adult patient weighing more than 110kg, the dose of acetylcysteine should be calculated using 110kg rather than actual weight. It should be noted that, for pregnant women, the dose of acetylcysteine should be calculated using a woman’s actual pregnant weight.6
In some circumstances intravenous administration of acetylcysteine is not possible. In these cases, the intravenous acetylcysteine preparation can be administered orally; this is an unlicensed route of administration and should only be considered after obtaining advice from the NPIS.5,6
After the 21-hour course of acetylcysteine is complete, most patients will be medically fit for discharge.6
However, before completion of the final infusion, a patient’s biochemical parameters (such as INR, creatinine, and liver function) should be checked.6
If all blood results are normal patients can be discharged safely, with advice to return to hospital if vomiting or abdominal pain occurs. All patients should be provided with a patient information sheet, which is available on the TOXBASE website (www.toxbase.org).6
If blood results are not normal, ongoing treatment with acetylcysteine may be required, details of which can be found on the TOXBASE website.6
Acute overdose with known time of ingestion
People who have ingested 75mg/kg or more of paracetamol in less than one hour are considered to have taken an acute overdose and should be referred directly to hospital.5,6 Administration of activated charcoal should be considered if paracetamol in excess of 150mg/kg is thought to have been ingested within the previous hour.5,6
If the time of an acute overdose of oral paracetamol is known, then decisions around whether or not to administer acetylcysteine can be made by plotting a patient’s plasma-paracetamol concentration (taken at least four hours after ingestion) against the time after ingestion on a treatment nomogram (see Figure 1) — patients require immediate treatment if their plasma-concentrations fall on or above the line on the nomogram.5,6
If the time of acute ingestion is not known, the treatment nomogram cannot be used.
Because the efficacy of acetylcysteine declines rapidly eight hours after ingestion of paracetamol, acetylcysteine should be administered immediately to patients who present eight to 24 hours after taking an acute overdose of more than 150 mg/kg of paracetamol, even if the plasma-paracetamol concentration is not yet available; acetylcysteine can be discontinued if the plasma-paracetamol concentration is later reported to be below the treatment line on the treatment nomogram, provided that the patient is asymptomatic and liver function tests, serum creatinine and international normalised ratio (INR) are normal.5,6
It is worth noting that the paracetamol treatment nomogram has changed recently. The most substantial difference is the replacement of “high-risk” and “normal” treatment lines with a single treatment line that applies to all patients. This new single line is equivalent to the old high-risk treatment line. In the past, some patients were considered at higher risk of liver damage than others based on the presence of factors such as chronic alcoholism, starvation and the use of hepatic enzyme inducing drugs. For these patients the threshold for treatment with acetylcysteine was lower, in terms of plasma-paracetamol concentration, than patients considered low risk, but the Commission on Human Medicines has since advised that these factors should no longer be considered in the assessment of paracetamol toxicity.4
A “staggered overdose” involves intentional ingestion of a potentially toxic dose of paracetamol over more than one hour whereas the inadvertent ingestion of a potentially toxic dose of paracetamol during its clinical use is termed “therapeutic excess”. In cases of staggered overdose or therapeutic excess the treatment nomogram discussed above is unreliable and, therefore, cannot be used for assessing risk of paracetamol toxicity;5,6 the treatment nomogram is also unsuitable for assessing toxicity in cases of overdose when the time of ingestion is unknown. The following points, however, should be considered:5,6
- Patients with clinical features of liver injury such as jaundice or abdominal (hepatic) tenderness should be treated urgently with acetylcysteine
- Serious toxicity can occur after ingestion of more than 150mg/kg in any 24-hour period and treatment with acetylcysteine should be commenced immediately (unless it is more than 24 hours since the last ingestion when the advice below should be followed)
- Rarely, toxicity can occur with doses of 75–150mg/kg within any 24-hour period and decisions to treat patients who have ingested doses of paracetamol within this range should be based on clinical judgement; for small individuals, doses of 75–150mg/kg in 24 hours may fall within the licensed dose, but ingestion of a licensed dose of paracetamol is not considered an overdose
- Clinically significant toxicity is unlikely if, 24 hours or longer after the most recent paracetamol ingestion, patients are asymptomatic, plasma-paracetamol concentrations are undetectable, and liver function tests, serum creatinine and INR are normal
Although there is some evidence suggesting that factors, such as the use of liver enzyme-inducing drugs, may increase the risk of hepatotoxicity, again the CHM has advised that these should no longer be used.
In this case
This case presents us with a situation of therapeutic excess. It sounds as if the person has had 6g of paracetamol in around 12 hours but dose and timing should be confirmed. Under such circumstances, the main factor that might influence your advice is probably the woman’s weight. The MHRA advises that doses less than 75mg/kg within 24 hours are unlikely to be toxic. It advises that patients require medical assessment, including blood tests, if they have taken chronic therapeutic excess (defined as more than a licensed dose for that individual and more than or equal to 75 mg/kg in any 24-hour period).
If any uncertainty exists regarding the dose or timing of ingestion the patient should be referred. TOXBASE advice is periodically up-dated. If a pharmacist does not have access to the latest TOXBASE advice or is uncertain on the advice given, then he or she should consult the NPIS directly (tel 0844 892 0111).
Kate Towers is BNF senior clinical writer and Shama Wagle is BNF lead editor.
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Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2014.11137924
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