Recommendations
Urgent
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.
If the patient has presented <8 hours after paracetamol overdose, treatment with acetylcysteine must be started within 8 hours of ingestion for maximum protection.[3]
Discuss the patient urgently with a senior 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 may be needed.[28][29]
Grade 2 encephalopathy; these patients are at high risk of decompensation and require more intensive monitoring.[28][29]
Discuss any patient who has had an overdose of intravenous paracetamol with your national poisons service as this is potentially very toxic.[3]
Intravenous paracetamol overdose is not covered in this topic.
Consider administration of activated charcoal if the patient presents within 1 hour of paracetamol ingestion and has ingested ≥150 mg/kg of paracetamol.[3]
Start an acetylcysteine infusion in a closely monitored area (which has capacity to treat an anaphylactoid reaction).[51] Treatment must be started within 8 hours of paracetamol ingestion to give maximum protection against liver damage.[3]
Key Recommendations
Be aware that paracetamol is known as acetaminophen in some countries.
If the patient does not meet the criteria for immediate treatment with acetylcysteine (see Acetylcysteine section below), wait for the results of blood tests. Determine need for treatment with acetylcysteine based on the time passed since paracetamol ingestion and results of blood tests, using the treatment nomogram for your region.
In the UK, use the nomogram produced by the National Poisons Information Service (NPIS).[27] MHRA: treatment nomogram for paracetamol overdose Opens in new window
Monitor all patients closely for acetylcysteine infusion reactions over the first few hours.[51]
Treat acute kidney injury conventionally.[3] Serum creatinine >300 micromoles/L is an indication for consideration of urgent liver transplant.[3] See Acute kidney injury.
For patients with hypoglycaemia, give supportive care as needed (with glucose and/or glucagon). See Non-diabetic hypoglycaemia.
Ensure the patient has access to psychological support if paracetamol was taken in the context of self-harm.[31] See Suicide risk mitigation.
Follow your local protocols for recommended monitoring for liver toxicity throughout and after the acetylcysteine infusion. Parameters (and the recommended intervals to monitor) vary according to the regimen used; these may include:
International normalised ratio (INR)
Urea and electrolytes
Alanine aminotransferase (ALT).
Test results indicate liver toxicity if:[3]
ALT has doubled (or more) since the admission measurement or
ALT ≥2 times the upper limit of normal or
INR >1.3 (in the absence of another cause, e.g., warfarin).
If there is evidence of liver toxicity:
Continue acetylcysteine
Follow local protocols, as recommended actions vary according to the acetylcysteine regimen used.
If you are uncertain, discuss individual patients with your local poisons information service (in the UK, the National Poisons Information Service [NPIS]). National Poisons Information Service: TOXBASE Opens in new window
Consider discharge if the patient does not meet the criteria for continuing acetylcysteine and has no symptoms suggestive of liver toxicity.[3] Give the patient verbal and written information on paracetamol overdose prior to discharge; advise them to return if they develop vomiting, abdominal pain, or jaundice.[3]
The aim of treatment is to prevent or minimise liver injury following paracetamol overdose.
Liver damage is minimised with acetylcysteine. This restores levels of glutathione, which detoxifies the hepatotoxic metabolite of paracetamol N-acetyl-p-benzoquinone imine (NAPQI).[51]
Address the underlying reason for paracetamol overdose.
Refer people with underlying mental illness.
Ensure the patient has written and verbal information about paracetamol overdose.
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]
International normalised ratio (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 (PT) >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.[28][29]
Grade 2 encephalopathy; these patients are at high risk of decompensation and require more intensive monitoring.[28][29]
Practical tip
Any patient with signs of acute liver injury should be managed in a specialist liver centre. Refer patients early, even if they do not initially appear to be significantly unwell, as it can be dangerous to transfer a patient when they have deteriorated clinically.[29]
Evidence: King’s College Criteria
The King’s College Criteria (KCC) are widely used worldwide to identify people with acute hepatotoxicity requiring immediate liver transplant. They are specific but have a low sensitivity, and there is debate on their impact on long-term survival.
Early and accurate identification of people needing emergency liver transplantation is important, and the KCC is the most common tool used globally.[52]
A systematic review (search date October 2001) compared KCC with other prognostic criteria including pH <7.30, serial prothrombin time, coagulation factor ratios, and the Acute Physiology and Chronic Health Evaluation II score (APACHE II).[53]
The review included 10 studies.
An APACHE II score of >15 performed the best overall (sensitivity 81% and specificity 92%), however it was only reported in one study.
Otherwise, KCC and pH <7.30 were the most accurate. They had a similar specificity (KCC: 92% [95% CI 81% to 97%] vs. pH <7.30: 89% [95% CI 62% to 97%]), however KCC was more sensitive (69% [95% CI 63% to 75%] vs. 57% [95% CI 44% to 68%]).
Another systematic review (search dates 2001 to 2015) compared the accuracy of KCC with the Model for End-stage Liver Disease (MELD).[54]
In people with acute liver failure from paracetamol overdose, KCC was better than MELD at predicting hospital mortality (KCC: sensitivity 58% [95% CI 51% to 65%], specificity 89% [95% CI 85% to 93%]; MELD: sensitivity 80% [95% CI 74% to 86%], specificity 53% [95% CI 47% to 59%]).
The low sensitivity is a limitation of the KCC as there may be patients requiring immediate liver transplant who are missed (false negative results).
It is unclear if using the KCC improves long-term survival.
A systematic review (search dates January 1989 to January 2007) looked at the survival benefit of using KCC.[55]
15 studies were included with data on people who met KCC but did not have a liver transplant (n=386). 10-year survival rate was 24.9% (95% CI 20.8 to 29.4%). However, there was wide variation between studies; survival without transplant was worse in studies from one much larger site, the King’s College Hospital (KCH) Liver Unit, compared with the other included sites (13.8% vs. 30.0%). This may be due to spectrum bias; if the KCC are applied to people too ill to undergo transplant then it will overestimate the performance of the criteria. In addition, people with the best prognosis may have been preferentially transplanted at the KCH Liver Unit, indicating the KCC may perform significantly worse at predicting death without transplant than previously estimated.
Data from the UK Transplant Support Service Authority Liver Transplant Audit showed survival rates for liver transplant for acute liver failure was 44% at 10 years.
Using these figures the authors modelled survival for an 18-year-old patient meeting KCC and found no difference in life expectancy (13.5 years with transplant vs. 13.4 years without transplant).
Note that survival without transplant following paracetamol-related acute liver failure has improved greatly over time, which will affect the prognostic models (such as KCC) and may fundamentally change the role of liver transplant in these patients.[56][57]
Treat acute kidney injury and hypoglycaemia conventionally.[3] See Acute kidney injury and Non-diabetic hypoglycaemia.
Practical tip
Acute kidney injury usually peaks 3 to 7 days after paracetamol ingestion but normally recovers.[3]
Consider administration of activated charcoal if the patient presents within 1 hour of paracetamol ingestion and has ingested ≥150 mg/kg of paracetamol.[3] Use caution in any patient who:
Is comatose or drowsy. Ensure their airway is protected as they are at risk of aspiration.[58]
Has reduced gastrointestinal motility as they are at risk of small bowel obstruction.[58]
Practical tip
Advise patients that activated charcoal may increase the risk of treatment failure of anticonvulsants and oral contraceptives (i.e., seizures, pregnancy) and that they should take precautions against these.[51]
Ensure the patient has access to psychological support if paracetamol was taken in the context of self-harm.[31] See Suicide risk mitigation.
Always follow local protocols, e.g., the National Poisons Information Service (TOXBASE) in the UK. National Poisons Information Service: TOXBASE Opens in new window
Management of paracetamol overdose with acetylcysteine depends on the risk of liver damage based on the dose and timing of ingestion.
If the patient is at risk of liver damage (see Indications for immediate treatment, below), immediately give acetylcysteine intravenously (see Dosing, below).[1]
If the patient is asymptomatic and has ingested <150 mg/kg, wait for blood results before considering treatment with acetylcysteine (see Treatment after results of blood tests, below).[3] If the patient has ingested <75 mg/kg it is unlikely that serious toxicity will occur, so in the absence of any symptoms, treatment with acetylcysteine is not needed.[3]
If treatment with acetylcysteine is not needed, seek advice from a senior colleague or the appropriate mental health team before discharging a patient, if they have taken an overdose with the intention of self-harm or suicide. See Suicide risk mitigation.
Only start an acetylcysteine infusion in a closely monitored area (which has capacity to treat an anaphylactoid reaction).[51] Treatment must be started within 8 hours of paracetamol ingestion to give maximum protection against liver damage.[3]
Give acetylcysteine even if the patient has a history of a previous adverse reaction as the benefits outweigh the risks.[51] Consider using a slower initial infusion of acetylcysteine in these patients to reduce the risk of a further reaction, as well as giving prophylactic treatment (e.g., antihistamines).[51]
Monitor all patients closely for acetylcysteine infusion reactions over the first few hours.[51]
See Adverse reactions to acetylcysteine, below for more information.
Be aware that vomiting is relatively common during intravenous acetylcysteine administration.[59] In clinical practice, manage with an anti-emetic (e.g., ondansetron).
Vomiting will not affect the efficacy of treatment.
Practical tip
If serum paracetamol concentrations are checked during acetylcysteine infusion, some chemical analysers may significantly underestimate serum paracetamol concentrations by as much as 40%, depending on serum acetylcysteine concentrations. The National Poisons Information Service (NPIS) in the UK recommends that you ensure results provided by their lab are not affected in this way. If in doubt, check with your lab.[3]
Consult your local protocol for guidance on choice of acetylcysteine regimen and dosing recommendations. Always discuss with a senior colleague.
In the UK, the Royal College of Emergency Medicine (RCEM) and the National Poisons Information Service (NPIS) endorse a 12-hour acetylcysteine infusion (Scottish and Newcastle Acetylcysteine Protocol [SNAP] regimen) for the treatment of paracetamol toxicity in adults as standard practice in the emergency department.[3][60] This is at odds with the Medicines and Healthcare products Regulatory Agency (MHRA)-approved 21-hour infusion which has historically been used.[61] The RCEM/NPIS endorsement is based on results from the 2014 SNAP study and further analyses of the SNAP regimen in 2019.[62][63] SNAP (12-hour infusion) demonstrated fewer side effects and similar efficacy at preventing liver injury compared with the 21-hour infusion, potentially reducing length of hospital stay.[60][63]
The SNAP regimen should only be used after discussion with a senior clinician, because SNAP is not licensed or endorsed by the MHRA.[3] The RCEM recognises that in some cases, including delayed presentation, and subject to senior clinical evaluation, the 21-hour infusion protocol may be more appropriate in practice.[60]
Evidence: Acetylcysteine
Acetylcysteine seems to be effective and safe in the treatment of paracetamol overdose; however, most of the evidence supporting its use has been low to very-low quality and there remains some uncertainty about the best regimen. Although there has historically been some uncertainty about the best regimen, data from the SNAP randomised controlled trial and subsequent prospective study have demonstrated similar efficacy and fewer side effects with a 12-hour acetylcysteine infusion compared with a 21-hour infusion.[62][63]
One Cochrane systematic review (search date January 2017) assessed interventions for paracetamol overdose.[5]
Acetylcysteine seemed to be more effective than placebo at reducing mortality in people with fulminant acute liver failure due to paracetamol overdose (1 study, n=50, Peto OR 0.29, 95% CI 0.09 to 0.94; low quality evidence, assessed using GRADE).
Although there were no trials comparing acetylcysteine with either dimercaprol or cysteamine, from an indirect comparison of the data in different studies it seems people given acetylcysteine experienced fewer adverse effects.
There was insufficient evidence to show if acetylcysteine was superior to methionine.
For most of the studies comparing different acetylcysteine regimens the primary outcome was adverse events. Overall there was uncertainty regarding which regimen was the most effective as most trials were underpowered to look at this outcome.
One trial (n=222), the 2014 SNAP study, compared a modified 12-hour acetylcysteine regimen with the standard 21-hour infusion.[62]
There were significantly fewer adverse reactions (vomiting, retching, need for anti-emetics, or anaphylactoid symptoms; GRADE low) with the modified regimen.[62]
There was no difference in hepatotoxicity (OR 0.67, 95% CI 0.11 to 4.08, GRADE very low), however the trial was underpowered to show this. No deaths were reported in either arm.
The authors of the Cochrane review concluded that acetylcysteine should be given to people at risk of toxicity (including those presenting with acute liver failure); however, more research is needed comparing different interventions, treatment protocols, and routes of administration to inform clinical practice.
In January 2017 the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK recommended that continued treatment with acetylcysteine may be necessary beyond 21 hours in some patients dependent on clinical evaluation.[61]
In this report the MHRA also referred to the 2014 SNAP study but noted that the Commission on Human Medicines had concluded this study did not provide sufficient evidence to recommend an off-label shortened regimen.[62]
The NACSTOP trial (published February 2019) was a multicentre, cluster-controlled trial which considered stopping acetylcysteine early in selected “very low risk” patients.[64]
It included people aged >16 years with paracetamol overdose who presented with normal serum ALT and creatinine, and had paracetamol levels <20 mg/L at 12 hours with normal ALT and creatinine at 12 hours.
Patients were allocated to a shortened infusion over 12 hours (n=50) or a standard 20-hour regimen (n=50).
No patients developed hepatic injury (defined as ALT doubling and peak ALT >100 IU/L at 20 hours after the start of treatment) or hepatotoxicity. There were also no deaths and no patient required a liver transplant.
One subsequent prospective study (published in 2019) compared the SNAP regimen with the standard 21-hour acetylcysteine regimen:[63]
3340 patients admitted with paracetamol overdose were included across multiple centres
1488 patients were treated with the 21-hour regimen and 1852 patients with the 12-hour regimen
Hepatotoxicity occurred in 64 (4.3%) patients who received the 21-hour regimen and in 67 (3.6%) patients who received the SNAP regimen (absolute difference -0.7%, 95% CI -2.1 to 0.6)
Antihistamine treatment (for acetylcysteine anaphylactoid drug reactions) was prescribed for 163 (11%) patients receiving the 21-hour regimen and 37 (2%) patients receiving the SNAP regimen (absolute difference 9.0% [95% CI 7.3 to 10.7])
No patients were readmitted to hospital with, or died from, liver failure within 30 days of discharge.
Unusual paracetamol poisoning
The NPIS in the UK is aware of a few patients developing severe liver toxicity after presenting with a serum paracetamol concentration that appears below the recommended threshold for antidote use (the treatment line on the nomogram).
In some of these patients, there have been errors in the history, stated dose, or timing of ingestion. In addition, multiple dose ingestion causes particular problems and may be responsible for some of these reports.
Discuss any patient with unusual poisoning with your local poisons information service. In the UK, contact the NPIS.[3] National Poisons Information Service: TOXBASE Opens in new window
Indications for immediate treatment before availability of blood test results
Acute single overdose: <8 hours since ingestion
Start treatment with acetylcysteine immediately without waiting for blood test results, if there is going to be a delay beyond 8 hours in obtaining the serum paracetamol concentration and the patient has ingested ≥ 150 mg/kg body weight paracetamol as an acute overdose (i.e., all doses taken within 1 hour).[3]
There is normally no indication to start acetylcysteine without a paracetamol blood concentration provided the result can be obtained and acted upon within 8 hours of ingestion.[3]
Treatment with acetylcysteine must be started within 8 hours of paracetamol ingestion for maximum protection.[3]
Acute single overdose: 8 to 24 hours since ingestion
Start treatment with acetylcysteine without delay if:[3]
It is thought that ≥150 mg/kg paracetamol (or an unknown amount) has been ingested as an acute overdose (i.e., all doses taken within 1 hour) or
There are clinical features of liver injury (e.g., jaundice, hepatic tenderness).
If the patient is asymptomatic and has ingested <150 mg/kg, wait for blood results before considering treatment with acetylcysteine.[3]
Acute single overdose: >24 hours since ingestion
Start treatment with acetylcysteine without delay if:[3]
It is thought that ≥150 mg/kg paracetamol (or an unknown amount) has been ingested as an acute overdose (i.e., all doses taken within 1 hour) or
There are clinical features of liver injury (e.g., jaundice, hepatic tenderness).
If the patient is asymptomatic and has ingested <150 mg/kg paracetamol, wait for the results of blood tests before starting treatment.[3]
Acute single overdose: time since ingestion uncertain
Start treatment with acetylcysteine without delay if time of ingestion is uncertain and all doses were taken within 1 hour.[3]
Staggered paracetamol overdose
Start treatment with acetylcysteine without delay in all patients who have ingested a staggered overdose (all tablets taken over a period of more than 1 hour).[3]
Therapeutic excess
Start acetylcysteine without delay if the patient has ingested a therapeutic excess and there are clinical features of liver injury (e.g., jaundice, hepatic tenderness).[3]
Treatment after results of blood tests
If the patient is not at risk of liver damage and therefore does not meet criteria for immediate treatment with acetylcysteine, wait for the results of blood tests.
Determine need for treatment with acetylcysteine based on the type of overdose (acute single overdose or therapeutic excess), time passed since paracetamol ingestion, and results of blood tests.
Acute single overdose: <24 hours since paracetamol ingestion
Give acetylcysteine if the serum paracetamol concentration is on or above the treatment line on the nomogram for your region, or there is evidence of liver injury (e.g., alanine aminotransferase [ALT] above the upper limit of normal).[3]
In the UK, use the nomogram produced by the National Poisons Information Service (NPIS).[27] MHRA: treatment nomogram for paracetamol overdose Opens in new window
Plot the measured serum paracetamol concentration against the time since ingestion on the treatment nomogram for your region; check the units carefully and use the correct scale.
If there is any uncertainty whether the patient’s serum paracetamol concentration is above or below the treatment line on the nomogram for your region, treat with acetylcysteine.[3]
Practical tip
Treat the patient with acetylcysteine if there is any uncertainty about whether the patient’s serum paracetamol concentration is above or below the treatment line on the nomogram for your region. Bear in mind that the nomogram is unreliable if the timing of ingestion is uncertain.
Check the limit of paracetamol detection of your laboratory if the patient presents more than 12 to 15 hours after ingestion.[3] Give acetylcysteine to any patient where the limit of paracetamol detection is higher than the threshold for treatment.
The lower limit of paracetamol detection recommended is 10 mg/L but some laboratories in the UK have a higher limit of detection than this. Laboratories that use this higher limit will not be able to identify a borderline toxic serum paracetamol concentration. For example, if they use a limit of 20 mg/L they will not be able to detect a borderline toxic serum paracetamol concentration after 13 hours as the treatment line drops below 20 mg/L after this time period.
Consider giving acetylcysteine if blood tests suggest acute liver injury (e.g., ALT or INR above the upper limit of normal) even if the serum paracetamol concentration is below the treatment line on the nomogram for your region. MHRA: treatment nomogram for paracetamol overdose Opens in new window[27]
Acute single overdose: >24 hours since paracetamol ingestion
Give acetylcysteine if blood tests show:[3]
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.
Any patient who is asymptomatic and presents more than 7 days after the last dose of paracetamol was ingested does not normally require further assessment if:[3]
They have had no new symptoms since the time of ingestion and
They have no history of chronic kidney or liver disease and
The timing of ingestion is certain.
Therapeutic excess
Start acetylcysteine if the patient has ingested excessive paracetamol, with intent to treat pain or fever and without self-harm intent (usually taken over >24 hours), if blood tests indicate a risk of hepatotoxicity:[3]
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 >10 mg/L.
Dosing
Consult your local protocol for guidance on choice of regimen and dosing recommendations. Always discuss with a senior colleague.
In the UK, the RCEM and the NPIS endorse a 12-hour acetylcysteine infusion (Scottish and Newcastle Acetylcysteine Protocol [SNAP] regimen) for the treatment of paracetamol toxicity in adults in the emergency department.[3][60] This is at odds with the MHRA-approved 21-hour infusion which has historically been used.[61]
The SNAP regimen should only be used after discussion with a senior clinician, because SNAP is not licensed or endorsed by the MHRA.[3] The RCEM recognises that in some cases, including delayed presentation, and subject to senior clinical evaluation, the 21-hour infusion protocol may be more appropriate in practice.[60]
Treatment is the same for special patient groups (patients who are pregnant or weigh more than 110 kg). However, calculate the acetylcysteine dose for these patients as follows:[3]
If the patient is pregnant, use the patient’s current pregnant weight
If the patient weighs more than 110 kg, calculate the dose using a maximum weight of 110 kg, rather than the patient’s actual weight.
The UK National Poisons Information resource, Toxbase, states to double the dose of acetylcysteine for patients on renal replacement therapy, but other sources may vary.[3]
Dilute acetylcysteine in 5% glucose; use 0.9% sodium chloride solution if glucose is unsuitable (e.g., for patients with diabetes).
Very rarely, oral therapy is required if available (e.g., complete absence of venous access in intravenous drug users).[3]
Practical tip
There is normally no indication to start acetylcysteine without a serum paracetamol concentration provided the result can be obtained and acted on within 8 hours of ingestion.[3] Acetylcysteine is virtually 100% effective in preventing liver damage when given within 8 hours of ingestion. After 8 hours, efficacy decreases sharply.[27]
Treatment with acetylcysteine must be started within 8 hours of ingestion for maximum protection.[3]
If the patient has taken an overdose and re-presents following assessment and discharge, manage as a new presentation.[3]
Monitor all patients closely for acetylcysteine infusion reactions over the first few hours.[51]
Adverse reactions to acetylcysteine are common, occurring in up to 30% of patients treated with the standard 21-hour regimen, usually during or soon after the first infusion, when large amounts are given rapidly.[3]
Adverse reactions are more likely if serum paracetamol concentrations are low or absent, and in women, patients with asthma, and those with a family history of allergy.[3]
Nausea, vomiting, flushing, urticarial rash, angioedema, tachycardia, and bronchospasm are relatively common. Hypotension and collapse are uncommon.[3] These symptoms interrupt treatment and may lead to reluctance to receive acetylcysteine in the future.[3]
In patients experiencing an adverse reaction temporarily stop the acetylcysteine.
Re-start acetylcysteine infusion once the reaction has settled. Consider slowing the infusion rate (e.g., administer the first bag over twice as long as usual; the normal infusion rate can be used for subsequent bags).[3]
Consider giving inhaled salbutamol for wheezing and antihistamines for skin reactions.[3][51]
Give acetylcysteine even if the patient has a history of a previous adverse reaction as the benefits outweigh the risks.[51] Consider using a slower initial infusion of acetylcysteine in these patients to reduce the risk of a further reaction.[51]
A history of anaphylactoid reactions is not a contraindication to intravenous acetylcysteine in patients with paracetamol overdose when antidote treatment is clinically indicated.[3] In people with previous anaphylactoid reactions to acetylcysteine, before starting an infusion, consider:[3]
Prophylactic treatment with an antihistamine (follow local protocols)
Pretreatment with nebulised salbutamol in patients with a history of bronchospasm following acetylcysteine.
Advise all patients to seek medical attention if symptoms develop after discharge.[3]
Practical tip
Hypersensitivity-like reactions that are attributed to acetylcysteine are likely to be anaphylactoid (e.g., rash, pruritus, vomiting, flushing, wheeze, and hypotension) and may not occur on repeated exposure to acetylcysteine as they are not immunologically mediated.[27][51]
Other serious adverse effects are due to giving excessive acetylcysteine due to dose calculation errors (e.g., lethal anaphylactoid reactions from 10-fold dosing errors).[51]
Less serious adverse effects such as nausea and vomiting are common.[51]
Review the patient when the results of blood tests are available.
Discontinue acetylcysteine if the patient is not at risk of liver toxicity. This would be if:[3]
The serum paracetamol concentration is not detectable (<10 mg/L)
International normalised ratio (INR) and alanine aminotransferase (ALT) are within normal ranges
The patient is asymptomatic
Serum creatinine is within normal range.
Practical tip
Discuss patients with a chronically elevated ALT (e.g., chronic liver disease) with your national poisons service.[3]
These patients may not require acetylcysteine treatment if the ALT and INR have not significantly changed from previously documented values.
Follow your local protocols for recommended monitoring for liver toxicity throughout and after the acetylcysteine infusion. Parameters (and the recommended intervals to monitor) vary according to the regimen used; these may include:
International normalised ratio (INR)
Urea and electrolytes
Alanine aminotransferase (ALT).
Test results indicate liver toxicity if:[3]
ALT has doubled (or more) since the admission measurement or
ALT ≥2 times the upper limit of normal or
INR >1.3 (in the absence of another cause, e.g., warfarin)
Practical tip
Be aware that treatment with acetylcysteine may slightly increase INR, even if there is no liver toxicity.[65]
If there is evidence of liver toxicity:
Continue acetylcysteine[3]
Follow local protocols, as recommended actions vary according to the acetylcysteine regimen used.
If you are uncertain, discuss individual patients with your local poisons information service (in the UK, the National Poisons Information Service [NPIS]). National Poisons Information Service: TOXBASE Opens in new window
Practical tip
Be alert to possible liver failure.
Treat acute kidney injury conventionally. See Acute kidney injury.
Acute kidney injury may occur with acute hepatic injury or without. Even a small rise in creatinine may be clinically significant. Acetylcysteine has not been tested as an antidote for this complication and there is uncertainty about its efficacy.[3]
Stop acetylcysteine infusion if:[3]
The INR is ≤1.3 or
The INR is falling towards normal on two consecutive blood tests, AND is <3.0.
Once INR is normal there is no need to treat rises in ALT with acetylcysteine.[3]
If the INR rises:[3]
By ≤0.4 (e.g., 1.1 to 1.5): discontinue acetylcysteine and consider discharging the patient if ALT is normal and there are no other indications for continuation of acetylcysteine.
By ≥0.5 (e.g., 1.1 to 1.6), in the absence of a rise in ALT: stop acetylcysteine treatment and recheck INR and ALT in 4-6 hours.
After 4-6 hours without acetylcysteine, consider discharging the patient if INR is unchanged or falling and ALT is less than two times the upper limit of normal. If these criteria are not met, restart acetylcysteine.
Practical tip
There is no clinical advantage to treating ALT rises with acetylcysteine after INR has normalised because this indicates restoration of synthetic hepatic function.[3]
If there is no evidence of liver toxicity, stop acetylcysteine and consider discharge.[3] See Discharge section below.
Consider discharge once acetylcysteine has been stopped and the patient has a normal serum creatinine level.
Before discharge, give the patient verbal and written advice to:[3]
Return to hospital if they develop vomiting, abdominal pain, or jaundice
Seek medical attention if they develop symptoms of adverse reaction to acetylcysteine:
Nausea, vomiting, flushing, urticarial rash, angioedema, tachycardia, and bronchospasm are relatively common
Hypotension and collapse are uncommon
Avoid paracetamol:
For the next 2 weeks if they have ongoing abnormal liver function but meet the criteria for stopping acetylcysteine
For the next 12 hours if they did not meet the criteria for acetylcysteine treatment but had an initial serum paracetamol concentration >20 mg/L.
Always seek advice from a senior colleague or the appropriate mental health team before discharging a patient if they have taken an overdose with the intention of self-harm or suicide. See Suicide risk management.
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