Recommendations
Urgent
Assess the patient using the Airway, Breathing, Circulation, Disability, Exposure (ABCDE) approach.[26]
Start treatment with acetylcysteine without delay in any of the following circumstances:[3]
Acute overdose (excessive doses of paracetamol taken within 1 hour, usually in the context of self-harm) - patient presenting <8 hours after acute ingestion and:
≥150 mg/kg body weight paracetamol has been ingested and there will be a delay beyond 8 hours after the overdose in obtaining the paracetamol level or
The treatment nomogram for your region categorises the patient as being at risk of liver injury (based on blood paracetamol levels taken ≥4 hours after the last ingestion), or there is any uncertainty about whether the patient's paracetamol concentration is above or below the nomogram line[27]or
There is evidence of liver injury (e.g., alanine aminotransferase [ALT] above the upper limit of normal).
Acute overdose - patient presenting 8-24 hours after acute ingestion and:
It is thought that ≥150 mg/kg paracetamol (or an unknown amount) has been ingested or
There are clinical features of liver injury (e.g., jaundice, hepatic tenderness) or
The treatment nomogram for your region categorises the patient as being at risk of liver injury, or there is any uncertainty about whether the patient's paracetamol concentration is above or below the nomogram line[27] or
There is evidence of liver injury (e.g., ALT above the upper limit of normal).
Acute overdose - patient presenting >24 hours after acute ingestion and:
It is thought that ≥150 mg/kg paracetamol (or an unknown amount) has been ingested or
There are clinical features of liver injury (e.g., jaundice, hepatic tenderness) or
ALT is above the upper limit of normal or
International normalised ratio (INR) >1.3 (in the absence of another cause, e.g., warfarin) or
Paracetamol concentration is detectable.
Acute overdose - time of ingestion unknown
Staggered overdose (excessive doses of paracetamol taken over longer than 1 hour, usually in the context of self-harm)
Therapeutic excess (excessive doses of paracetamol taken with intent to treat pain or fever and without self-harm intent) and:
There are clinical features of liver injury (e.g., jaundice, hepatic tenderness) or
ALT is above the upper limit of normal or
INR >1.3 (in the absence of another cause, e.g., warfarin) or
Paracetamol concentration is detectable.
If there is uncertainty about whether the presentation was due to therapeutic excess.
Discuss the patient urgently with a senior colleague if any features of hepatic necrosis are present. These include:
Right subcostal pain and tenderness[3]
Nausea and vomiting[3]
Jaundice[3]
Acute kidney injury[3]
Hepatic encephalopathy[3]
INR >1.3[3]
Hypoglycaemia.[28]
Trigger urgent referral to hepatology if there are indications for urgent liver transplantation:[3]
Arterial pH <7.3
Hepatic encephalopathy grade 3 or 4
Serum creatinine >300 micromoles/L
Prothrombin time >100 seconds
Serum lactate >3.5 mmol/L on admission or >3.0 mmol/L 24 hours post-paracetamol ingestion or after fluid resuscitation.
Escalate to critical care if the following are present:
The serum paracetamol concentration is very high (>700 mg/L) and is associated with coma and elevated lactate level; renal replacement therapy may be needed[3]
Grade 3 or 4 encephalopathy; tracheal intubation to protect the airway is recommended[29]
Grade 2 encephalopathy; these patients are at high risk of decompensation and require more intensive monitoring.[29][28]
Assess the patient’s mental capacity to stay for assessment and treatment, and for signs of mental illness. Always involve senior support.[28][30]
Key Recommendations
Be aware that paracetamol is known as acetaminophen in some countries.
Assess the risk of liver toxicity by asking the patient:[3]
How much paracetamol they have taken; find out the formulation and dose ingested
The recommended maximum adult dose is 4 g (or 75 mg/kg) in 24 hours so anything above this is an overdose - toxicity is unlikely with <75 mg/kg ingested within a 24-hour period[3]
Bear in mind that patients with bodyweight <50 kg are at increased risk of toxicity and overdose at therapeutic doses.[2]
Over what period the paracetamol was ingested and the intention; this is categorised as:[3]
Acute overdose (excessive doses of paracetamol taken within 1 hour, usually in the context of self-harm)
Staggered overdose (excessive doses of paracetamol taken over longer than 1 hour, usually in the context of self-harm)
Therapeutic excess (excessive doses of paracetamol taken with intent to treat pain or fever and without self-harm intent).
How long has elapsed since they took the last dose of paracetamol.
Ask the patient if their paracetamol overdose was intentional. Ensure the patient has access to psychological support if paracetamol was taken in the context of self-harm.[31] See Suicide risk mitigation.
If more than 8 hours have passed since paracetamol ingestion, take blood immediately for urgent measurement of serum paracetamol concentration (before acetylcysteine is given if possible).[3]
Wait until 4 hours after paracetamol ingestion before taking blood samples if less than 8 hours have passed since ingestion.[3]
Also take venous blood gas and blood samples for:[3]
Urea and electrolytes
Bicarbonate
Glucose
Liver function tests
Prothrombin time and INR
Full blood count.
It is common practice to take an arterial blood gas if the venous blood gas shows significant abnormalities.
Be aware that patients are often asymptomatic at initial presentation, although nausea and vomiting are common.[1] Very rarely, coma and severe metabolic acidosis occur in patients with very high serum paracetamol concentrations (>700 mg/L).[3]
Bear in mind that examination is usually normal unless the patient develops acute liver failure.
In the community, refer any patient who has taken an overdose of paracetamol to hospital for immediate medical assessment if they meet any of the following criteria:[3]
Overdose due to intention to self-harm (irrespective of reported dose)
Symptomatic
Ingestion of ≥75 mg/kg of paracetamol over a period of 1 hour or less
Uncertain time, dose, or circumstance
Staggered overdose
Ingestion of paracetamol as a therapeutic excess and one of the following criteria:
More than a licensed dose for that individual (4 g in an adult) AND ≥75 mg/kg in any 24-hour period
More than the licensed dose for that individual (4 g in an adult) but <75 mg/kg/24 hours on each day of the last 72 hours.
Patients typically present within a few hours of taking an overdose, usually either asymptomatically or with nausea and vomiting.[1]
Nausea and vomiting are very common features[3]
Severe metabolic acidosis and coma can, very rarely, occur with very high plasma paracetamol concentrations[1][3]
Their presence usually implies mixed overdose.[1]
Loin pain, haematuria, and proteinuria after the first 24 hours may indicate acute kidney injury.[3] Oliguria is an early indicator of impaired kidney function[32]
Abdominal pain may occur as a later feature (12-36 hours) in people with severe poisoning[3]
After 2 to 3 days there may be features of hepatic necrosis:[3]
Establish a history of the paracetamol overdose - was it:
An acute overdose (excessive doses of paracetamol taken within 1 hour, usually in the context of self-harm)?
A staggered overdose (excessive doses of paracetamol taken over longer than 1 hour, usually in the context of self-harm)?
Therapeutic excess (excessive paracetamol taken with intent to treat pain or fever and without self-harm intent)?
Discuss any patient who has had an overdose of intravenous paracetamol with your national poisons service as this is potentially very toxic. In the UK, contact the National Poisons Information Service (NPIS).[3] National Poisons Information Service: TOXBASE Opens in new window
Bear in mind that patients with bodyweight <50 kg are at increased risk of toxicity and overdose at therapeutic doses of oral and intravenous paracetamol.[2]
Practical tip
Paracetamol taken in therapeutic excess is common. This usually occurs over more than 24 hours, but may occur over less than 24 hours, and is not associated with intentional self-harm. Therapeutic excess can involve ingestion of excessive doses of the same paracetamol product or inadvertent use of more than one paracetamol-containing product at the same time.[3]
Specifically ask/ascertain:
What time did the patient take the overdose?[3]
This is important as it will determine when to measure the serum paracetamol concentration (serum concentrations measured less than 4 hours after ingestion cannot be interpreted) and whether to wait for a serum paracetamol concentration before giving acetylcysteine.[3]
Start acetylcysteine without delay if the time of ingestion is unknown.[1][3]
How much paracetamol was taken?[3]
Serious toxicity may occur in patients ingesting >150 mg/kg in any 24-hour period.
Rarely, toxicity can occur with ingestions between 75 and 150 mg/kg within any 24-hour period.
Doses consistently <75 mg/kg in any 24-hour period are very unlikely to be toxic, although the risk may be increased if this dose is repeatedly ingested over 2 or more days.
Calculate the toxic dose of paracetamol for special patient groups as follows:[3]
If the patient is pregnant, use the patient’s pre-pregnancy weight
If the patient weighs >110 kg, calculate the toxic dose using a maximum of 110 kg, rather than the patient’s actual weight.
Was the overdose intentional, accidental, or a therapeutic error?
Assess suicide risk if it was intentional. See Suicide risk mitigation.
Is there a risk of repetition of the overdose?
Establish why the patient took the overdose. This may be due to intention to self-harm or lack of understanding of safe use of paracetamol.
Ascertain if there is a history of previous paracetamol overdose and if there is a history of misuse of other painkillers.
Did the patient take any other drugs, alcohol, or other painkillers with the paracetamol?
Assess the patient’s mental capacity to stay for assessment and treatment and for signs of mental illness. Always involve senior support.[33][31]
Practical tip
Apply the 2005 Mental Capacity Act if based in England and Wales.
Ask about risk factors that increase the risk of liver injury following paracetamol overdose:[1]
Glutathione deficiency. Patients at risk include those with:
Malnourishment (e.g., not eating because of dental pain, fasting for more than a day)
Eating disorders (e.g., anorexia, bulimia)
Psychiatric disorders
Chronic illness (e.g., HIV, cystic fibrosis)
Cachexia
Alcohol-use disorder.
Long-term treatment with drugs that induce liver enzymes (cytochrome P450 inducers):
Carbamazepine
Phenobarbital
Phenytoin
Primidone
Rifampicin
Rifabutin
Efavirenz
Nevirapine
St John’s wort.
Ask about the patient’s psychiatric history and history of self-harm.
Ask about the patient’s social history and current support.
This will determine whether they can be discharged safely.
Examination is usually normal unless the patient develops acute liver injury. Assess for:[1]
Jaundice
May be difficult to detect in people with dark skin.
In practice, most easily seen in the sclera and best seen in natural light by pulling down the lower eyelid and asking the patient to look up.
Tender hepatomegaly[34]
Palpate the abdomen.
Ensure you percuss the upper and lower borders of the liver. In practice, sometimes lung pathology such as COPD can push the liver down and give a false impression of hepatomegaly.
Hepatic encephalopathy
Assess for the presence and severity of encephalopathy. See Hepatic encephalopathy.
Involve critical care support if there is grade 3 or 4 encephalopathy, as tracheal intubation to protect the airway may be needed.[28][29] Critical care should also be involved if there is grade 2 encephalopathy, as these patients are at risk of decompensation and require intensive monitoring.[28][29] The most common clinical classification used to describe the severity of hepatic encephalopathy is the West Haven criteria:[35][36]
Grade 4: coma, with or without response to painful stimuli.
Grade 3: drowsy but rousable, unable to perform mental tasks, disorientation to time and place, marked confusion, amnesia, occasional fits of rage, speech present but incomprehensible.
Grade 2: drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behaviour, intermittent disorientation. Asterixis is obvious.
Grade 1: mild confusion, euphoria, or depression, decreased attention, slowing of ability to perform mental tasks, irritability, disorder of sleep pattern such as inverted sleep cycle. Asterixis can be detected.
Grade 0: subclinical; normal mental status but minimal changes in memory, concentration, intellectual function, coordination.
Hypoglycaemia.[28]
Practical tip
There are many other causes of asterixis apart from liver failure, such as respiratory failure, structural brain lesions, and certain drugs (e.g., antipsychotics).[37] Test for asterixis by extending both of the patient's arms, dorsiflexing the wrists, and spreading the fingers to observe for the 'flap' at the wrist.[37]
Blood tests are needed in most patients who have taken an excessive dose of paracetamol.
Use clinical judgement to determine whether blood tests are indicated if the patient is well and has no signs of hepatotoxicity, the history is reliable, and paracetamol was taken as a therapeutic excess that meets one of the following criteria:[3]
The maximum dose ingested is consistently less than the licensed 24-hour dose for that patient (e.g., 4 g in an adult) AND consistently <75 mg/kg for that patient over the preceding 24-hour period
The maximum dose ingested is more than the licensed 24-hour dose for that patient (e.g., 4 g in an adult) but <75 mg/kg/24 hours on each day of the last 72 hours AND the patient does not have risk factors that increase the risk of hepatotoxicity, such as:
Long-term treatment with drugs that induce liver enzymes including carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John's wort
Regular consumption of alcohol in excess of recommended amount
Likely glutathione deficiency, resulting from e.g., an eating disorder, cystic fibrosis, HIV, starvation, cachexia.
Practical tip
Be aware that reported doses of therapeutic excess may be unreliable and you should take this into account when making judgements about the need for further assessment.[3]
Serum paracetamol concentration
Use serum paracetamol concentration to risk-stratify the likelihood of liver injury and to determine whether treatment with acetylcysteine is needed.[3]
Practical tip
A serum paracetamol concentration measured less than 4 hours after ingestion cannot be interpreted.[3]
Acute single overdose <8 hours since ingestion
Wait until 4 hours after paracetamol ingestion before taking the sample in patients who have ingested paracetamol as an acute overdose (i.e., all doses taken within 1 hour).[3]
Consider repeating the serum paracetamol concentration at 6 hours after ingestion if the result at 4 hours is below the threshold for treatment with acetylcysteine and the patient has taken concomitant medications that decrease gastric emptying (e.g., opioids) as these can falsely decrease the result.[38]
Staggered overdose or therapeutic excess
Take the sample at least 4 hours after the last dose of paracetamol was ingested in patients who have ingested all paracetamol tablets over more than 1 hour but less than 24 hours.[3]
Consider repeating the serum paracetamol concentration at 6 hours after ingestion if the result at 4 hours is below the threshold for treatment with acetylcysteine and the patient has taken concomitant medications that decrease gastric emptying (e.g., opioids) as these can falsely decrease the result.[38]
Acute single overdose >8 hours since ingestion
Take blood immediately for urgent measurement of serum paracetamol concentration (before acetylcysteine is given if possible) in patients who have ingested paracetamol as an acute overdose (i.e., all doses taken within 1 hour).[3]
Risk stratification
Assess the risk of liver injury using the treatment nomogram for your region to determine whether acetylcysteine is needed.[3][27] MHRA: treatment nomogram for paracetamol overdose Opens in new window
Evidence: Use of biomarkers to assess risk of liver injury
Biomarkers may help to predict which patients with paracetamol overdose will develop hepatotoxicity, and therefore help identify those that require further treatment with greater accuracy than serum paracetamol concentrations. However, none of the novel markers are in widespread clinical use.
One study used data from two prospective UK multicentre studies (a derivation [n=985] and a validation cohort [n=202]) to assess the accuracy of microRNA-122 (miR-122), keratin-18, high mobility group box-1 (HMGB1), and glutamate dehydrogenase (GLDH).[39] ALT levels >100 U/L were used as the reference standard for liver injury.
All performed significantly better than serum paracetamol concentrations, which had a very low sensitivity and an area under the curve (AUC) of around 0.5.
miR-122 identified at presentation which patients would develop acute liver injury in both the derivation cohort (AUC 0.97, 95% CI 0.95 to 0.98) and the validation cohort (AUC 0.97, 95% CI 0.95 to 0.99).
Results were similar for HMGB1 (derivation AUC 0.95; validation AUC 0.98) and full-length keratin-18 (derivation AUC 0.95; validation AUC 0.93), however GLDH did not perform as well as the other biomarkers tested.
Combining miR-122, HMGB1, and keratin-18 predicted acute liver injury with a sensitivity 99.9% and specificity 98%.
The authors noted that more research is required to evaluate how well these markers predict rarer outcomes (e.g., liver failure and death), and larger trials are required before they can be considered for routine clinical use.
Liver function tests
Suspect acute liver injury if:
Alanine aminotransferase (ALT) is above the upper limit of normal.[3]
Practical tip
ALT rises rapidly in severe paracetamol poisoning and is commonly abnormal at first presentation to hospital. A raised ALT at presentation may also indicate that the overdose was taken earlier than suggested by the history.[3]
Prothrombin time and INR
Measure the prothrombin time and international normalised ratio (INR) to monitor the severity of liver failure and also to assist in patient stratification for optimal benefit in liver transplantation.
Discuss urgently with a senior colleague if prothrombin time >30 seconds or INR is >1.3.
A higher cut-off of >100 seconds is used to identify patients who may require liver transplantation. However, it is common in practice to escalate patients to a senior colleague at this lower cut-off of 30 seconds.
Re-check INR at recommended intervals throughout and after the acetylcysteine infusion (follow your local protocols).
Suspect acute liver injury if INR is >1.3 in the absence of other causes (e.g., warfarin).[3]
Blood glucose
May show hypoglycaemia.[28]
Urea, creatinine, and electrolytes
Creatinine will be raised in acute kidney injury. Discuss the patient urgently with a senior colleague if serum creatinine >300 micromoles/L as this is an indication for urgent liver transplant.[3] This may occur as part of acute liver injury (hepatorenal syndrome) or, rarely, in the absence of acute liver injury.[3]
Re-check creatinine in 8 to 12 hours if it has risen significantly.[3]
Practical tip
Even a small rise in creatinine may be clinically significant following paracetamol overdose.[3]
Full blood count
This may show leukocytosis, anaemia, or thrombocytopenia.[40][41][42]
Venous or arterial blood gas
Take a venous blood gas initially. If this shows significant abnormalities, it is common practice to take an arterial blood gas.
A blood gas may show lactic acidosis in two scenarios:
Early after a large paracetamol ingestion[43]
Lactic acidosis is commonly severe and associated with coma. Most patients do not develop liver damage if treated with acetylcysteine.[43]
Late after development of liver failure[43]
Elevated lactate in these patients strongly predicts high mortality.[43]
Serum lactate >3.5mmol/L on admission or >3.0mmol/L 24 hours post-paracetamol ingestion or after fluid resuscitation is an indication for urgent liver transplantation.[3]
Salicylate level
Order if you suspect concurrent salicylate poisoning.[44] See Salicylate poisoning.
Urine drug screen
Order in the following groups:
Vulnerable people
Involve a senior colleague and follow your local safeguarding protocol if there is a positive result as this may indicate abuse
Patients with suspected mental illness
Drug intoxication may mimic some mental illnesses[45]
People who display signs of drug misuse.
Refer any patient who has taken an overdose of paracetamol to hospital for immediate medical assessment if they meet any of the following criteria:[3]
Overdose due to intention to self-harm (irrespective of reported dose)
Symptomatic
Nausea and vomiting are very common features
Ingestion of ≥75 mg/kg of paracetamol over a period of 1 hour or less
Uncertain time, dose, or circumstance of ingestion
Staggered overdose
Ingestion of paracetamol as a therapeutic excess and one of the following criteria:
More than a licensed dose for that individual (4 g in an adult) AND ≥75 mg/kg in any 24-hour period
More than the licensed dose for that individual (4 g in an adult) but <75 mg/kg/24 hours on each day of the last 72 hours.
Practical tip
If there is any doubt about the severity of paracetamol overdose in the community, discuss with the nearest emergency department consultant (or National Poisons Information Service [NPIS] if based in the UK), as management in secondary care may be necessary.
How to take a venous blood sample from the antecubital fossa using a vacuum needle.
How to obtain an arterial blood sample from the radial artery.
How to perform a femoral artery puncture to collect a sample of arterial blood.
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