Paracetamol poisoning is the most common overdose seen in the UK.
Paracetamol is a commonly used anti-pyretic and analgesic that can be bought over the counter. It has an excellent safety profile and is used for a variety of conditions. However, in overdose, it can lead to drug-induced liver injury (DILI). Within the UK, paracetamol overdose is the most common cause of acute liver failure (ALF) requiring liver transplantation.
Paracetamol overdose is commonly seen within the emergency department and most hospitals will have a local policy for its management.
Local policies will be based on advice from the national poisons information service (NPIS), which provides a clinical toxicology database known as ‘Toxbase’. This provides information on the diagnosis, treatment and management of patients who have been exposed to a wide range of medications, chemicals, plants and animals.
Risk assessment is based on amount of paracetamol ingested (mg/kg) and time since ingestion.
All patients presenting after taking an overdose of paracetamol should have the following risk assessment as a minimum:
Doses < 75 mg/kg are unlikely to cause toxicity unless staggered. Doses >150 mg/kg are associated with serious or fatal adverse effects from toxicity and total doses > 12 g are potentially fatal.
It is essential to understand and characterise the type of paracetamol ingestion as it determines management.
This refers to the ingestion of a potentially toxic dose of paracetamol within one hour or less.
Serious toxicity is unlikely if a patient has ingested <75 mg/kg. If a patient has ingested > 75 mg/kg, are symptomatic, or need urgent psychiatric assessment (if taken in context of self-harm), hospital admission is warranted.
This refers to excessive ingestion of paracetamol over a period longer than one hour, usually in the context of self-harm.
Serious toxicity may occur in patients who have ingested > 150 mg/kg in any 24 hour period. Rarely, toxicity may occur for ingestions between 75-150 mg/kg. Doses consistently < 75 mg/kg in any 24 hour period are unlikely to be toxic. However, if paracetamol above the recommended daily dose (4g/24 hours in adults) is ingested for the two preceding days or more, the risk increases.
All patients that have taken a staggered overdose should be referred to hospital for assessment.
If the time of ingestion is unknown patients should be treated as a ‘staggered overdose’.
This refers to a delay between the time of overdose and presentation to medical care.
This may be in the context of an acute overdose or staggered overdose. If a significant delay is suspected, treatment is usually initially first whilst awaiting further investigations.
This refers to the unintentional use of excess paracetamol with the intent to treat an underlying problem (e.g. pain, fever) without intention of self-harm.
Patients should have ingested paracetamol at a dose greater than the licensed daily dose (4g/24 hours) and ≥75 mg/kg over 24 hours. Patients may have inadvertently taken paracetamol in addition to a paracetamol containing product (e.g. co-codamol). If there is uncertainty whether the presentation is unintentional therapeutic excess, patients should be managed as a staggered overdose.
Paracetamol is primarily metabolised in the liver to non-toxic metabolites.
Once ingested, paracetamol reaches peak concentration at 4 hours with an average half life of 2 hours. This may be significantly increased in the presence of hepatic dysfunction.
Paracetamol is primarily metabolised in the liver. This occurs via conjugation with the addition of glucuronide to form a water soluble metabolite that can be excreted in the urine. When there is excess paracetamol, such as with overdose, conjugation become saturated and paracetamol is converted into the metabolite N-acetyl-p-benzoquinoneimine (NAPQI).
NAPQI has a short half-life and is usually conjugated by the addition of glutathione, which is then renally excreted. When glutathione stores are depleted, excess NAPQI binds to hepatocellular proteins and results in oxidative damage, mitochondrial dysfunction and ultimately hepatocellular injury. Anything that effects glutathione reserves may increase the risk of severe hepatotoxicity such as fasting, excess alcohol consumption and certain drugs.
Patients may be completely asymptomatic in the early stages following overdose. Common symptoms include nausea, vomiting and abdominal pain.
Rarely, patients who have taken a significant overdose with very high plasma paracetamol concentrations may develop early metabolic acidosis, raised lactate and possibly coma. This is a separate clinical syndrome to the development of ALF, which is a direct drug effect of paracetamol on the functioning of mitochondria, which usually resolves with falling paracetamol levels.
Around 12-36 hours following overdose patients may experience abdominal pain. At 48-72 hours, patients may develop clinical features due to hepatic necrosis, which include right upper quadrant pain, nausea, vomiting, jaundice, acute kidney injury (i.e. oligo-/anuria) and hepatic encephalopathy (HE). The development of HE with coagulopathy (INR >1.5) is indicative of ALF and patients require urgent transfer to a transplant unit for further assessment.
Some patient may require urgent liver transplantation whereas others may show spontaneous recovery but need supportive care in intensive care during this process. Clinical recovery can take up to 3 weeks and complete hepatic recovery seen on histology can take several months.
Patients may be asymptomatic in the early stages of paracetamol overdose.
Many patients may be asymptomatic and show spontaneous recovery without a major effect on liver function. Others, particularly with significant overdoses, may have a wide range of clinical features due to severe hepatocellular injury.
Diagnosis of paracetamol overdose is based on the history, but investigations are needed to assess for complications.
The diagnosis is based on the history, which may be from the patient, relative/friend or ambulance crew who have found empty packets of paracetamol. It is essential to consider paracetamol in any patient presenting with a mixed overdose or where the medication is unknown.
Any patient who has ingested paracetamol in the context of self-harm needs hospital admission for medical assessment and urgent psychiatric input.
Other reasons for hospital admission include:
A series of blood tests are essential to assess for hepatic damage, extra hepatic organ dysfunction and determine patients that may need urgent referral to a transplant centre.
The paracetamol ingestion graph or ‘nomogram’ is used to determine if treatment with N-acetylcysteine (NAC) is needed.
The paracetamol nomogram is used to plot paracetamol concentration against time from ingestion. If the paracetamol concentration lies on or above the treatment line, NAC should be administered. This is used for patients who have ingested paracetamol over one hour or less and presented within 8 hours. As the plasma paracetamol concentration reaches its peak at 4 hours, it is important not to take a paracetamol level within 4 hours of the last ingestion.
Example of paracetamol nomogram. Not to scale (not for clinical use)
Patients who have a delayed presentation, or where the paracetamol level will not be available within 8 hours from last ingestion, NAC is started whilst awaiting investigations. Paracetamol levels can be interpreted up to 24 hours, but any detectable level of paracetamol beyond 16 hours is concerning.
The principle treatment of a paracetamol overdose is N-acetylcysteine.
The principle treatment of paracetamol overdose is the intravenous administration of NAC. NAC has multiple proposed mechanisms of action. Critically, it is a precursor to glutathione, which means that administration increases the glutathione concentration available to bind NAPQI.
NAC is given as a standard 21 hour regimen, which is based on the patients weight. It comprises three consecutive infusions.
After the 21 hour regimen, bloods test are usually taken to look for any signs of hepatic impairment. If there is any evidence of significant coagulopathy, deranged liver function tests or abnormal renal function the patient should be discussed with the liver transplant centre. At this point, the third infusion of NAC is usually given continuously back-to-back until further advice.
Anaphylactoid reactions to intravenous NAC is common and seen in up to 30% of patients treated with the 21-hour regimen. It usually occurs soon after the first infusion with features of nausea, vomiting, urticarial rash, angioedema, tachycardia, and bronchospasm. Shock is uncommon.
If this develops, temporarily stop the infusion, consider chlorphenamine (anti-histamine) and nebulised salbutamol. Once the reaction has settled, restart the infusion. Can consider slowing the infusion rate of the first bag to over 2 hours.
NOTE: an anaphylactoid reaction produces the same clinical picture of anaphylaxis but is not IgE-mediated
Deciding when to initiate and continue NAC depends on the time and type of paracetamol ingestion.
All patients with a suspected paracetamol overdose should be managed according to a local treatment algorithm or follow the treatment algorithm from Toxbase. There are different algorithms depending on the type of ingestion (acute versus staggered), timing of presentation (< 8 hours, 8-24 hours, >24 hours) and presence or absence of hepatic damage.
NOTE: each diagram represents a simplified version of the treatment algorithm. Always check local guidelines or Toxbase.
At the end of the standard 21-hour infusion of NAC, patients need to undergo repeat blood tests for LFTs, U&Es, INR and venous blood gas.
Treatment may be stopped when:
Treatment with NAC should be continued when:
NOTE: if isolated rise in INR <0.5 from admission value, stop NAC and repeat INR in 4-6 hours. If INR falling or unchanged and ALT <2x upper limit of normal, no further treatment required.
Paracetamol overdose is the most common cause of ALF requiring liver transplantation in the UK.
Paracetamol overdose can lead to life-threatening ALF requiring urgent referral to a liver transplant centre for consideration of liver transplantation. These patients require management in an intensive care unit with specialist hepatology input. For more information see our notes on acute liver failure.
The decision to refer a patient to a liver transplant centre is based on guidance by the European association for study of the liver (EASL). In addition, the decision to allocate an urgent liver transplant is based on the King’s college criteria.
Any patient who has ingested paracetamol in the context of self-harm needs an urgent psychiatric assessment.
Liaison Psychiatry refers to a dedicated team that can provide psychiatric input in general hospitals for patients who have mental health problems. This is critical for patients who have presented with self-harm or overdose. Traditionally, overdose and poisoning represents up to 10% of medical admissions.
The liaison psychiatry team are able to assess a patients ongoing suicidal risk and need for ongoing mental health input. Some of the considerations the team can assess include:
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