Definition

Ingestion of more paracetamol than the liver can safely conjugate, either as a single acute overdose, an overdose staggered over more than an hour, or repeated supratherapeutic dosing.

Epidemiology

Paracetamol is among the commonest agents in UK self-poisoning and a leading cause of acute liver failure. Most presentations are deliberate single ingestions, but repeated therapeutic excess in a small, unwell or malnourished adult is the pattern most often missed.

Pathophysiology

At therapeutic doses paracetamol is glucuronidated and sulphated, with a small fraction oxidised by cytochrome P450 to N-acetyl-p-benzoquinone imine (NAPQI) and detoxified by glutathione. In overdose the conjugation pathways saturate and glutathione is exhausted, so NAPQI binds hepatocyte proteins and causes centrilobular necrosis. Coagulopathy, acidosis, hypoglycaemia, acute kidney injury and encephalopathy follow in severe cases. Acetylcysteine works by restoring glutathione, which is why it is most effective before necrosis is established.

First principles

Acetylcysteine replaces the glutathione that has run out, so timing decides everything

Acetylcysteine regenerates hepatic glutathione and neutralises N-acetyl-p-benzoquinone imine (NAPQI) before it binds hepatocyte proteins. Given within 8 hours of a single ingestion it prevents hepatotoxicity in almost every patient. Started later it still helps, but the benefit falls as covalent binding proceeds. A well patient with normal liver tests at 4 hours is the expected finding, not reassurance.¹

The nomogram answers one question and only one

It applies to a single ingestion taken over less than an hour with a reliable time. The treatment line runs from 100 mg/L at 4 hours to 15 mg/L at 15 hours. Before 4 hours absorption is incomplete, so a low level means nothing. Beyond 15 hours the line is unreliable and the decision becomes clinical.^2,1,3

Break the timing assumption and you treat first, test second

Ingestion staggered over more than an hour, an unknown time, or presentation beyond 8 hours all take the nomogram out of the decision to start. Start acetylcysteine immediately and take the bloods at the same time. The level then informs only whether treatment can stop at 12 hours. Waiting wastes the window in which the drug works.^2,1,3

Twelve hours is a minimum, not a course

The SNAP regimen (Scottish and Newcastle Acetylcysteine Protocol) delivers 300 mg/kg over 12 hours, but the drug stops when the blood tests allow it. Paracetamol below 10 mg/L, a normal alanine aminotransferase (ALT) that has not doubled since admission, an INR of 1.3 or less and no symptoms are all required. Otherwise the infusion continues.^3,4,5

Poisoning and self-harm are treated in parallel, not in sequence

A deliberate ingestion is an episode of self-harm whatever the level shows. Physical treatment takes priority while the patient is unstable, but the psychosocial assessment is arranged alongside it rather than bolted on at discharge. NICE also forbids using a risk scale to decide who is discharged.⁶

Presentation

Presentation ranges from an asymptomatic patient minutes after a deliberate overdose to jaundice and encephalopathy days later. Establish the formulation, the total dose in mg/kg, the exact time of every tablet, the body weight and any co-ingestants, because those five items decide the whole pathway.^3,1,7

Cardinal features

No symptoms and a normal examination in the first 24 hours, even after a clearly toxic dose
Nausea, vomiting and right-upper-quadrant pain appearing from about 24 hours
Jaundice, hepatic tenderness and rising transaminases at 48 to 72 hours
Ingestion of a combination product such as co-codamol or a cold and flu remedy that the patient did not count as paracetamol
Repeated supratherapeutic dosing in a small, unwell or malnourished adult rather than one large deliberate overdose

Red flags

Encephalopathy, hypoglycaemia or metabolic acidosis at any point after the overdose
INR above 2, arterial pH below 7.3 or creatinine above 200 micromol/L, each of which means phoning a liver unit
Ingestion staggered over more than 1 hour, an unknown time of ingestion, or presentation more than 8 hours after a toxic dose
Intravenous paracetamol exposure, age under 16, body weight under 40 kg, pregnancy or renal replacement therapy
Airway compromise or reduced consciousness, which usually means a co-ingestant rather than paracetamol itself

Investigations

Timed plasma paracetamol concentration

For a single ingestion with a reliable time presenting within 8 hours, sample at 4 hours after ingestion, or on arrival if already past 4 hours. Plot the result against the treatment line running from 100 mg/L at 4 hours to 15 mg/L at 15 hours.

Expected finding: On or above the line means treat. A sample taken before 4 hours cannot exclude toxicity however low it is, and the line is unreliable beyond 15 hours or after any staggered ingestion.

^2,3,1

Ingested dose in mg/kg

Divide the maximum plausible total paracetamol dose by body weight, capping the weight used at 110 kg. This number drives the decision whenever no interpretable level is available.

Expected finding: Above 150 mg/kg is potentially toxic and warrants treatment. Between 75 and 150 mg/kg, discuss with a senior or the National Poisons Information Service (NPIS). Below 75 mg/kg with a confident history is unlikely to harm.

^3,4

Liver, renal and metabolic bloods

Send alanine aminotransferase (ALT), INR, U&E, creatinine, venous gas, glucose and FBC at presentation. Repeat them 10 hours into treatment, so the result is back before the second infusion finishes.

Expected finding: Normal results at presentation are expected and exclude nothing. A rising ALT, an INR above 1.3, acidosis or hypoglycaemia signals established injury and moves the patient towards the liver unit thresholds.

^4,3,7

Co-ingestants, glucose and pregnancy

Check capillary glucose and an ECG in any unwell or mixed overdose. Ask specifically about combination tablets, which add an opioid. Test for pregnancy where relevant: the toxic dose is calculated on pre-pregnancy weight while the acetylcysteine dose uses current weight.

Expected finding: A co-ingestant may need its own antidote and can cause deterioration long before any hepatic injury appears.

^1,3

Management

Step	Detail	Source
Resuscitate, weigh the patient and get the current pathway	ABCDE, capillary glucose and a measured weight. Contact the National Poisons Information Service (NPIS) through its clinical database TOXBASE for children, pregnancy, weight under 40 kg, intravenous paracetamol exposure, renal replacement therapy or mixed overdose. Prescribe on your trust's pre-printed acetylcysteine chart: the doses below are national, the chart is local.^8,3,1	National Poisons Information Service TOXBASE; Royal Cornwall Hospitals SNAP protocol v2.0 (2024)
Quantify the ingestion and give charcoal only inside the hour	Calculate the maximum dose in mg/kg with the weight capped at 110 kg. Above 150 mg/kg is potentially toxic; the therapeutic maximum is eight 500 mg tablets in 24 hours. Consider activated charcoal 50 g by mouth within 1 hour of ingestion, but only if the patient is alert enough to drink it, never if drowsy.^3,9,10	BNF activated charcoal monograph; Royal Cornwall Hospitals SNAP protocol v2.0 (2024); NHS medicines information
Take the timed level when the ingestion is single and timed	Arrived before 4 hours: wait and sample at exactly 4 hours. Arrived between 4 and 8 hours: sample now. Plot against the line from 100 mg/L at 4 hours to 15 mg/L at 15 hours, and treat if on or above it. Send alanine aminotransferase (ALT), INR, U&E, creatinine, venous gas and glucose with it.^2,3,1	MHRA Drug Safety Update, treating paracetamol overdose with intravenous acetylcysteine
Start acetylcysteine without a level when the timing is broken	Three triggers to treat blind: ingestion staggered over more than 1 hour, an unknown time, or more than 8 hours since a potentially toxic dose. Start acetylcysteine immediately and take the bloods at the same time. Never plot a staggered or unknown-time ingestion at all. Beyond 8 hours the level decides only whether you can stop.^1,2,3	NHS Greater Glasgow and Clyde paracetamol overdose guideline; MHRA Drug Safety Update
Give the 12-hour SNAP acetylcysteine regimen	Adult 40 kg or more: acetylcysteine 100 mg/kg in 200 mL glucose 5% intravenously over 2 hours, then 200 mg/kg in 1 litre over 10 hours immediately afterwards. Total 300 mg/kg over 12 hours. Under 40 kg: same mg/kg as 50 mg/mL then 10 mg/mL solutions. Cap the weight at 110 kg. Sodium chloride 0.9% if glucose 5% is unsuitable.^5,11,12	BNF acetylcysteine monograph, paracetamol overdose 12-hour SNAP regimen; MHRA ceiling weight advice
Know why it is SNAP and not the 21-hour regimen	The Royal College of Emergency Medicine (RCEM) recommends the SNAP (Scottish and Newcastle Acetylcysteine Protocol) 12-hour regimen as default practice in every emergency department. It gives equal hepatoprotection with fewer reactions, and TOXBASE supports it. The licensed 21-hour alternative is 150 mg/kg over 1 hour, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours.^11,12,5,13	RCEM position statement, May 2023; MHRA authorised posology; NHS Highland, TOXBASE-supported SNAP protocol
Treat an anaphylactoid reaction and restart the infusion	Flushing, urticaria, wheeze, vomiting or hypotension early in the infusion is a rate-related anaphylactoid reaction, not an allergy. Pause the infusion for 30 minutes, give chlorphenamine 10 mg intravenously and nebulised salbutamol 5 mg for bronchospasm, then restart. A previous reaction does not bar a further course.^1,2,4	NHS Greater Glasgow and Clyde paracetamol overdose guideline; MHRA Drug Safety Update; East Kent Hospitals SNAP guideline v1.7
Decide at 12 hours whether to stop or continue	Send paracetamol, alanine aminotransferase (ALT), INR and U&E at 10 hours so the result is back before the second bag ends. Stop only if paracetamol is below 10 mg/L, ALT is normal and not double the admission value, INR is 1.3 or less and the patient is asymptomatic. Otherwise repeat 200 mg/kg over 10 hours, with no further loading dose.^4,3	East Kent Hospitals SNAP guideline v1.7 (2024); Royal Cornwall Hospitals SNAP protocol v2.0 (2024)
Escalate to a liver unit before the transplant criteria are met	Discuss any patient with an INR above 2, arterial pH below 7.3, creatinine above 200 micromol/L, hypoglycaemia or encephalopathy. Super-urgent transplant listing uses the King's College criteria, the thresholds for prioritising a liver graft. These are pH below 7.25 beyond 24 hours, or INR above 6.5 with creatinine above 300 micromol/L and grade 3 to 4 encephalopathy (drowsy or comatose).^7,14	NHS Greater Glasgow and Clyde acute liver failure guideline; NHS Blood and Transplant POL195/20
Complete the psychosocial assessment and discharge safely	Refer every self-harm presentation to liaison psychiatry for psychosocial assessment as soon as possible after arrival, and never use a risk scale to decide discharge. Discharge requires the blood criteria met, an agreed safety plan and written advice to return for vomiting, abdominal pain, jaundice, drowsiness or bleeding.^6,15,10	NICE NG225; Guy's and St Thomas' patient information

Illustrations

Paracetamol metabolism and glutathione depletionDiagram showing therapeutic conjugation pathways, formation of NAPQI in overdose, glutathione depletion and hepatocyte injury.PassFinals · original

Timed level and acetylcysteine decision pathwayFlow diagram distinguishing a known single acute ingestion suitable for timed nomogram plotting from staggered or uncertain ingestions treated immediately.PassFinals · original

Progression from overdose to acute liver failureClinical timeline from early nonspecific symptoms through hepatic injury, coagulopathy, encephalopathy and critical-care or transplant referral red flags.PassFinals · original

Differentials

Single acute ingestion

All tablets taken within 1 hour with a reliable time. The only pattern in which the 4 to 15 hour nomogram can be used.

Staggered overdose

Taken over more than 1 hour. The nomogram is invalid; start acetylcysteine on the calculated dose rather than waiting for a level.

Repeated therapeutic excess

Above the licensed dose over 24 hours or longer, often during illness. Decided on history, alanine aminotransferase and INR, not a single level.

Unknown time of ingestion

No reliable timing. Treat first; the level then informs stopping rather than starting.

Mixed overdose

Co-ingestants, especially the opioid in combination tablets, may cause harm well before the liver does.

Complications

Acute liver failure with encephalopathy and coagulopathy
Acute kidney injury, sometimes without severe liver injury
Metabolic acidosis, hyperlactataemia and hypoglycaemia
Anaphylactoid reaction to acetylcysteine
Repeat self-harm and continued access to medicines

Prognosis

Treated within 8 hours of a single ingestion, serious hepatotoxicity is rare. Prognosis worsens with delayed or staggered presentation and with rising INR, acidosis, hypoglycaemia, encephalopathy or renal failure, which mark the transition to acute liver failure and possible transplantation.

Guidelines

TOXBASE paracetamol overdose guidance (National Poisons Information Service)
Use of the SNAP regimen for the treatment of paracetamol toxicity in adults and children (Royal College of Emergency Medicine, 2023)
Intravenous N-acetylcysteine for paracetamol overdose: reminder of authorised dose regimen (Medicines and Healthcare products Regulatory Agency, 2017)
Treating paracetamol overdose with intravenous acetylcysteine: new guidance (Medicines and Healthcare products Regulatory Agency, 2014)
Self-harm: assessment, management and preventing recurrence (NG225) (National Institute for Health and Care Excellence, 2022)
Liver transplantation: selection criteria and recipient registration (POL195) (NHS Blood and Transplant, 2026)

Paracetamol overdose