Paracetamol overdose

• Paracetamol, also called acetaminophen in the United States and Canada, relieves pain and fever at therapeutic doses, but in overdose it can produce fatal hepatic necrosis. ^[1][4]
• Patients are often well for the first day. Hepatotoxicity becomes visible in the days that follow; patients are often asymptomatic in the first 24 hours. ^[4]
• Acetylcysteine is the specific antidote. Given within 8 hours of an acute ingestion it is close to completely protective against liver injury; after that window protection falls away. ^[3][5]
• In the United Kingdom a single Rumack-Matthew treatment line joining 100 mg per litre at 4 hours and 15 mg per litre at 15 hours after ingestion replaces the older high-risk and low-risk lines. ^[3][4]
• When the timing is doubtful or the ingestion was staggered over more than one hour, give acetylcysteine without waiting for a level, because the nomogram does not apply. ^{[3] [2]}
• For patients who already meet the King's College Criteria for poor prognosis, discuss transplant early. The key criteria are an arterial pH under 7.30 after resuscitation, or the combination of prothrombin time over 100 seconds, creatinine over 3.4 mg per dL and grade III or IV encephalopathy. ^[2]

By the end of this page you should be able to:

1. Explain why paracetamol is harmless at normal doses and hepatotoxic in overdose, from enzyme saturation to zone 3 necrosis. ^[2]
2. Recognise the early and late phases of paracetamol poisoning and know which tests decide management. ^[2][5]
3. Plot an acute plasma paracetamol concentration on the Rumack-Matthew nomogram and state the United Kingdom treatment line. ^[3][4]
4. Write the acetylcysteine regimen for a child or adult, including loading dose, maintenance doses, infusion times and stopping rules. ^[5]
5. Manage a staggered, an unknown-time and a repeated supratherapeutic overdose without the nomogram. ^[3][5]
6. Apply the King's College Criteria and arrange the correct referral when liver failure is developing. ^[2][4]

Paracetamol overdose is exposure to more paracetamol than the liver can handle by its normal conjugation pathways. The spectrum of presentation falls into four patterns. ^[2][4]

• Acute single overdose. A large amount taken in one hour or less, usually in the context of self-harm. ^[4]
• Staggered overdose. Excessive paracetamol taken in divided doses over more than one hour. ^[3][4]
• Repeated supratherapeutic ingestion. Paracetamol taken repeatedly above the daily therapeutic dose for analgesia or fever, often without any intent to self-harm. ^[5]
• Therapeutic excess. Paracetamol above the licensed daily dose but at therapeutic intent, often because more than one paracetamol-containing product has been used. ^[4]

Paracetamol itself is a familiar and generally safe analgesic and antipyretic. The danger is a metabolite, not the parent drug. ^[2][5]

Paracetamol is the most common drug taken in overdose in the United Kingdom and a leading cause of acute liver failure there. ^[4] It also dominates overdose statistics in North America, where 64,263 single-substance paracetamol exposures were reported to the National Poison Data System in 2024. ^[2] Overall, acetaminophen toxicity is the leading cause of acute liver failure in the United States. ^[1]

A repeated theme in the literature is accidental harm: in one major review about half of cases come from unintentional overdoses rather than deliberate self-harm. ^[1] This is one reason why asking about all medicines a patient takes, including cold remedies, matters as much as the headline dose. ^[2]

Mechanism of the exposure. Overdose in young children is usually a therapeutic misadventure by a caregiver, sometimes with unsupervised access to medicines. In adolescents and adults it is commonly self-harm. Repeated supratherapeutic ingestion is often a problem in febrile children with poor oral intake, or in adults using several products at once. ^[2]

Conditions that increase hepatotoxicity. The liver ordinarily conjugates NAPQI with glutathione; any state that lowers glutathione or speeds NAPQI production raises the risk for the same ingested dose. ^[2]

• Chronic alcohol use, poor nutrition, fasting, eating disorders and reduced oral intake. ^[2]
• Underlying liver or kidney disease. ^[2]
• Older age. ^[2]
• Cytochrome P450 inducers such as ethanol, tobacco smoking, isoniazid, rifampin, phenytoin, phenobarbital, barbiturates and carbamazepine. ^[2]
• Concurrent use of acetaminophen with non-steroidal anti-inflammatory drugs, which has been linked to extra kidney risk. ^[2]

Age and susceptibility. Healthy children between 1 and 6 years are less susceptible to hepatotoxicity from a single acute ingestion. Medical toxicologists often raise the treatment threshold in that group from 150 mg per kilogram to 200 mg per kilogram. ^[2] As a safety rule, the 24-hour dose of oral paracetamol in children and adolescents under 60 kg should not exceed 75 mg per kilogram per day or 4 grams per day, whichever is less. ^[2]

Paracetamol is rapidly absorbed from the stomach and small intestine after an oral dose. Serum concentration peaks at one to two hours, and peak plasma levels are reached within 4 hours of an overdose of an immediate-release preparation. ^[2] The elimination half-life is about 2 hours (range 0.9 to 3.25 hours). ^[2]

In ordinary use the liver metabolises most paracetamol by conjugation to non-toxic, water-soluble compounds that are excreted in the urine. ^[2] A smaller fraction is oxidised by the cytochrome P450 enzymes CYP2E1, 1A2, 2A6 and 3A4 to a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). ^[2] NAPQI has an extremely short half-life and is normally conjugated with glutathione, a sulfhydryl donor, and then excreted by the kidneys. ^[2]

In an overdose, or when the maximum daily dose is exceeded for a long period, conjugation becomes saturated and more drug is pushed down the oxidative pathway. ^[2] Studies in animal models and human data consistently point to the same problem: NAPQI is produced in amounts that exceed the glutathione store available for conjugation. ^[2]

When hepatic glutathione is depleted by approximately 70 percent, NAPQI covalently binds to the cysteinyl sulfhydryl groups of hepatocellular proteins and forms NAPQI-protein adducts. ^[2] That binding starts an escalating cascade of oxidative damage and mitochondrial dysfunction, and the inflammatory response that follows propagates hepatocellular injury and death. ^[2]

Necrosis is not random. It is centrilobular, in zone III of the liver lobule, because those hepatocytes carry the greater concentration of CYP enzymes and therefore generate more NAPQI. ^[2] Enzymes that leak from dying hepatocytes produce the rising alanine aminotransferase and aspartate aminotransferase. Acute renal injury occurs in the same way through analogous enzymatic reactions in the kidney, leading initially to acute tubular necrosis. ^[2][5]

Hepatocellular necrosis can develop after as little as 7.5 grams of paracetamol, and doses of 150 mg per kilogram or greater have been associated with hepatotoxicity. ^[4][5]

Acetylcysteine is the antidote. It acts through several routes rather than one. ^[2]

• It is a precursor of glutathione, replenishing the stores that conjugate NAPQI. ^[2]
• It enhances sulfate conjugation of unmetabolised paracetamol. ^[2]
• It is anti-inflammatory and antioxidant. ^[2]
• It has positive inotropic effects. ^[2]
• It increases local nitric oxide, improving microcirculatory blood flow and oxygen delivery to peripheral tissues. ^[2]

The microvascular effects are part of why acetylcysteine still reduces morbidity and mortality when given after hepatotoxicity has already begun. ^[2] It is maximally hepatoprotective within 8 hours of an acute ingestion, but it should be given even outside that window, because it may still improve outcome in established fulminant failure. ^[2][5]

Peak levels with extended-release tablets may occur after 4 hours. Intravenous paracetamol, used in anaesthetic practice since 2004 in the United Kingdom, produces peak plasma levels immediately rather than after oral absorption. ^[4] For both, the traditional oral nomogram must be used with care and local guidance or poison centre advice should be sought. ^[4][5]

Patients are often asymptomatic in the first 24 hours, with nausea, vomiting, right upper quadrant pain and progressive derangement of liver function tests becoming apparent after about 18 hours. ^[4] Because there may be little to see at first, every suspected overdose is taken seriously from the outset. ^[3][4]

As injury evolves the clinical picture broadens through four phases. ^[2][4]

1. Early phase, around the first 24 hours. Often no symptoms. Nausea, vomiting, pallor, diaphoresis, right upper quadrant discomfort and non-specific malaise when present. Blood tests are usually normal. ^[4]
2. Hepatic injury phase. Right upper quadrant pain and tenderness, rising alanine aminotransferase and aspartate aminotransferase, rising bilirubin and prolongation of prothrombin time or INR. Renal function may begin to deteriorate. ^[2][4]
3. Fulminant phase. Peak hepatotoxicity, which may follow in the next few days. Jaundice, coagulopathy, hepatic encephalopathy, hypoglycaemia, metabolic acidosis, acute kidney injury and, in the worst cases, cerebral oedema and multi-organ failure. ^[2][4]
4. Recovery phase. If the patient survives without transplantation, liver function usually returns to normal, with no long-term cirrhosis. ^[2]

A massive overdose may present earlier with coma and severe metabolic acidosis, and co-ingested opioids or sedatives can dominate the picture. ^[2]

Complications of the poisoning itself include acute tubular necrosis, hepatorenal syndrome, encephalopathy, life-threatening haemorrhage, liver failure, renal failure and death. ^[2]

The main task is to decide how ill the liver is, and how far along the injury has progressed. Paracetamol overdose can be confused with other acute liver injuries. ^[2]

Every assessment starts with the story and a clock: time of first ingestion, amount and formulation, number of divided doses, other substances, alcohol, medicines and meals. ^[2][5]

Laboratory tests. ^[5]

• Plasma or serum paracetamol concentration, taken no earlier than 4 hours after ingestion because earlier levels may not reflect the peak. ^[5]
• Alanine aminotransferase and aspartate aminotransferase for hepatocellular injury. ^[5]
• Bilirubin. ^[5]
• International normalised ratio and prothrombin time. ^[5]
• Creatinine and blood urea nitrogen for renal function. ^[5]
• Blood glucose and electrolytes. ^[5]
• Arterial blood gas when severe poisoning, metabolic acidosis or fulminant failure is suspected. ^[4][5]

Timing of the paracetamol level. ^[4][5]

• If the time of ingestion is unknown, give a loading dose of acetylcysteine immediately and take levels to decide whether treatment continues. ^[5]
• If the patient presents more than 8 hours after ingestion and the time is known, give the loading dose immediately and take a level. ^[5]
• If the patient presents less than 8 hours after ingestion but the result will not be available within 8 hours, or there is clinical evidence of toxicity, give the loading dose and complete three doses over 21 hours. ^[5]

Extended-release acetaminophen. ^[5] When an extended-release product is taken and the 4-hour concentration is below the treatment line, take a second sample at 8 to 10 hours after ingestion. If the second value reaches or crosses the treatment line, treat. ^[5]

Other imaging and tests. Cardiac monitoring, electrocardiography and a co-ingestion screen are guided by the history and by local protocols. The evidence reviewed here does not support routine biopsy or advanced imaging in paracetamol overdose. ^[2]

There is no blood test that by itself makes a diagnosis of paracetamol overdose in the way a throat swab diagnoses streptococcus. The diagnosis rests on history plus the plasma paracetamol concentration. ^[2][5]

Minimum potentially toxic exposures. ^[2]

• In adults, hepatotoxicity becomes likely after a single ingestion of 7.5 to 10 grams. ^[2]
• In children, a single acute ingestion of 150 mg per kilogram can be toxic. ^[2]
• In healthy children aged 1 to 6 years, the threshold is often raised to 200 mg per kilogram. ^[2]
• Repeated supratherapeutic ingestion is a separate problem, and the nomogram does not apply. ^[5]

The Rumack-Matthew nomogram. ^[2][3][4][5]

Plot the plasma paracetamol concentration against the time since ingestion, on a semi-logarithmic chart, from 4 hours to 24 hours. Treatment is given when the level is on or above the treatment line. ^[3][5] The nomogram is not valid for: ^[4][5]

• Presentation under 4 hours after ingestion, or after 24 hours. ^[5]
• Unknown or unreliable time of ingestion. ^[5]
• A staggered overdose. ^[3][5]
• Repeated supratherapeutic ingestion. ^[5]
• Modified-release or extended-release preparations. ^[5]

The United Kingdom line. ^[3][4] Following the 2012 review by the Medicines and Healthcare products Regulatory Agency, the United Kingdom uses one treatment line joining 100 mg per litre at 4 hours and 15 mg per litre at 15 hours after ingestion. ^[3][4] This single line removed the old high-risk and low-risk nomograms, which had required the clinician to estimate hepatotoxic risk factors such as chronic alcohol misuse, drug interactions and malnutrition. ^[3]

Where doubt exists over timing, including an ingestion that occurred over one hour or more, the instruction is to give acetylcysteine without delay and not to use the nomogram. ^[3][4]

Treat every reported paracetamol overdose as an emergency, including accidental therapeutic excess and suspected self-harm. ^[3][4] The airway, breathing and circulation come first, with oxygen when needed and careful fluid resuscitation. Any patient with altered consciousness, self-harm intent or a severe co-ingestion needs the appropriate psychiatric and safeguarding assessment in addition to the medical care. ^[3][4]

For a single acute ingestion within about 2 hours, activated charcoal can be considered, although the supporting evidence for improved outcomes is limited. ^[1]

Indications in acute single ingestion. ^[3][4][5]

• Plasma paracetamol at or above the treatment line at 4 hours or more after ingestion.
• Ingestion of more than 150 mg per kilogram in one hour or less, with presentation within 8 hours and a delay of 8 hours or more before the level will be available. ^[2][4]
• Presentation 8 to 24 hours after an acute ingestion of more than 150 mg per kilogram. ^[4]
• Clinical evidence of hepatotoxicity even when the concentration is below the line. ^[4][5]
• When the timing is unknown or doubtful, or the ingestion is staggered, give acetylcysteine immediately without waiting for a level. ^[3][4]

Dose. ^[5] Give 300 mg per kilogram intravenously in total, as three sequential doses: 150 mg per kilogram over 1 hour, then 50 mg per kilogram over 4 hours, then 100 mg per kilogram over 16 hours. ^[5]

Why 60 minutes for the first bag. ^[3] Most dose-related adverse reactions appear in the first hour of the infusion. Extending the loading infusion from 15 to 60 minutes was recommended specifically to reduce those reactions, and the evidence from the loading dose trials supports the practice. ^[3][5]

Weight and pregnancy. ^[6] Patients weighing less than 40 kg use a paediatric acetylcysteine regimen and adjusted dilution to avoid fluid overload. ^[5][6] For patients weighing more than 110 kg, a body weight of 110 kg is used for calculating both the toxic paracetamol dose in mg per kilogram and the acetylcysteine dose. ^[6] In pregnancy the toxic dose is calculated from pre-pregnancy or booking weight, while the acetylcysteine dose is calculated from current weight. ^[6]

Anaphylactoid reactions. ^[3][5] UK guidance no longer lists hypersensitivity as a contraindication to acetylcysteine, because the reactions are anaphylactoid and not immunologically mediated; they may not recur on re-exposure. ^[3] The United States label still lists a previous hypersensitivity reaction as a contraindication. ^[5] In either case, flush or erythema during the loading infusion is common and often settles spontaneously, while bronchospasm, hypotension or wheeze needs the infusion stopped, treated with antihistamines or bronchodilators, and then carefully restarted. ^[3][5]

Stopping or continuing acetylcysteine. ^[5] At the end of the maintenance dose check the paracetamol concentration, alanine aminotransferase, aspartate aminotransferase and INR. Continue beyond the standard course if paracetamol is still detectable, or if transaminases are still rising, or if the INR remains elevated, and seek poison centre advice for repeated dosing. ^[5] If the time of ingestion is known and the concentration is below the treatment line after 4 hours, there is minimal risk of hepatotoxicity and acetylcysteine is not required. ^[5]

Staggered and unknown-time overdose. ^[3][4] Give acetylcysteine without delay. ^[3] If ingestion has taken place over more than one hour, use the worst-case timing, anchoring the paracetamol concentration to the earliest dose, and repeat the level two hours after the first. ^[4] For an overdose spread over roughly a day, manage according to the 8 to 24 hour pathway rather than time-anchoring to any single ingestion. ^{[4] [5]}

Repeated supratherapeutic ingestion. ^[5] The Rumack-Matthew nomogram is not used. Diagnosis rests on total dose taken, timing, symptoms and laboratory values, principally alanine aminotransferase and aspartate aminotransferase alongside the paracetamol level. ^[5]

Acetylcysteine regimens. ^[5][6] The 21-hour 3-bag regimen above is standard. A 12-hour Scottish and Newcastle anti-emetic pre-treatment regimen is used in some United Kingdom centres; it delivers the same total dose over 12 hours rather than 21. ^[6] It is recognised by TOXBASE but is not approved by the Medicines and Healthcare products Regulatory Agency, and practice varies between hospitals. ^[6] Follow local guidance and the TOXBASE entry. ^[6]

When to involve a liver transplant centre. ^[2][4] Refer early when severe poisoning markers are present: INR over 2.0 at 24 hours, over 4 at 48 hours, or over 6 at 72 hours; creatinine over 200 micromol per litre; hypoglycaemia; metabolic acidosis despite rehydration; hypotension despite resuscitation; or encephalopathy. ^[4] Patients approaching King's College Criteria should be discussed with hepatology and transplant surgery before they meet the criteria, because transfer becomes more hazardous late in the course. ^[2]

Supportive management in established failure includes meticulous airway care, glucose control, correction of acidosis and renal support. Reference is made to local liver protocols; specific thresholds for dialysis or ventilation are not stated here. ^[4]

Massive accidental dosing errors with intravenous paracetamol occur because of millilitre-to-milligram confusion and by giving a fixed 1 gram dose to adults under 50 kg. ^[4] Both the Medicines and Healthcare products Regulatory Agency and the National Patient Safety Agency have issued alerts on this issue, and weight-based dosing with clear charts reduces the risk. ^[4]

Pregnancy. ^[6] Delaying treatment in a pregnant woman with potentially toxic levels increases the risk of maternal and fetal morbidity and mortality, since paracetamol and acetylcysteine cross the placenta. ^[5][6] Calculate the toxic dose from pre-pregnancy or booking weight and the acetylcysteine dose from current weight. ^[6]

Children. ^[2] Use paediatric acetylcysteine dose tables and adjusted dilution. Children under 6 years are less susceptible, but this must not encourage complacency; any child with an ingestion above 150 mg per kilogram needs assessment. ^[2] In children over 10 kg the intravenous paracetamol dose should not exceed 15 mg per kilogram or 60 mg per kilogram per day; children under 10 kg receive 7.5 mg per kilogram up to 30 mg per kilogram per day. ^[4]

Malnutrition, chronic alcohol use and drug interactions. ^[2] These patients may have reduced glutathione and altered CYP activity, so their risk at a given dose is higher. The older dual nomogram attempted to capture this, and the newer single line manages it by treating anyone on or above the line. ^[3]

Obesity. ^[6] Use 110 kg for mg-per-kilogram calculations in patients above 110 kg. ^[6]

The modified King's College Criteria identify patients who are unlikely to survive without liver transplantation after an isolated paracetamol overdose. ^[2] Paracetamol overdose is also the commonest reason in the United Kingdom to consider emergency transplantation. ^[4]

King's criteria for paracetamol-induced acute liver failure. ^[2]

• Arterial pH under 7.30 after fluid resuscitation, alone; or
• Prothrombin time over 100 seconds (INR over 6.5) together with creatinine over 3.4 mg per dL and grade III or IV hepatic encephalopathy.

Any one criterion is enough to prompt urgent referral. Other early predictors include elevated lactate and raised phosphate, which may identify the same patients sooner. ^[2]

• Paracetamol should be used at or below its licensed daily dose, and patients should be warned about overlapping cold and flu remedies. ^[2]
• Keep paediatric liquid paracetamol at one standard concentration (160 mg in 5 mL) and use the dosing syringe supplied with the product. ^[2]
• Store all medicines out of reach of children and provide clear written and verbal dosing instruction. ^[2]
• For patients with cirrhosis, paracetamol remains one of the safer analgesics when the total daily dose is limited to 2 to 3 grams in three divided doses; overdose in this group is more dangerous. ^[4]

Where plasma paracetamol assay, acetylcysteine or a liver transplant service is unavailable, the safest approach is prevention and early referral. ^[1][4]

• Recognise that young children and febrile patients with poor intake are the higher-risk group. ^[2]
• Treat suspected overdose empirically when time is uncertain or the nomogram unavailable, following local guidelines or poison centre advice. ^[3]
• Give glucose promptly if hypoglycaemia is present, because it predicts poor outcome. ^[4]
• Refer anyone with encephalopathy, acidosis, coagulopathy or renal injury to the highest available level of care. ^[4]
• Where intravenous acetylcysteine is not available, oral acetylcysteine is an alternative in some systems, although intravenous treatment is preferred where possible. ^[2]

• Paracetamol is a safe analgesic at therapeutic doses, but its metabolite NAPQI can cause hepatic necrosis in overdose. ^[2][5]
• Conjugation saturates, glutathione falls by about 70 percent, and NAPQI binds hepatocellular proteins; zone III (centrilobular) necrosis follows. ^[2]
• Susceptibility is increased by alcohol, malnutrition, fasting, liver or kidney disease, age and cytochrome P450 inducers. ^[2]
• Expect little to no symptoms for the first 24 hours, with transaminases rising after 18 hours and peak injury between day 3 and day 4. ^[2][4]
• The United Kingdom uses one treatment line: 100 mg per litre at 4 hours to 15 mg per litre at 15 hours after ingestion. ^[3][4]
• Give acetylcysteine immediately for staggered, unknown-time or clinically toxic overdoses; do not wait for a level. ^[3][4]
• The standard acetylcysteine regimen is 150 mg per kilogram over 1 hour, then 50 mg per kilogram over 4 hours, then 100 mg per kilogram over 16 hours, totalling 300 mg per kilogram over 21 hours. ^[5]
• Acetylcysteine works best within 8 hours, but it should not be withheld in late presenters with established failure. ^[2][5]
• Stop or continue treatment using detectable paracetamol, rising transaminases or persisting INR elevation. ^[5]
• Young children are less susceptible to an acute single ingestion, but repeated therapeutic dosing in febrile children with poor intake is dangerous. ^[2]
• King's College Criteria for paracetamol: arterial pH under 7.30 after resuscitation alone, or prothrombin time over 100 seconds with creatinine over 3.4 mg per dL and grade III or IV encephalopathy. ^[2]
• With good supportive care and timely acetylcysteine, mortality in paracetamol hepatotoxicity is less than 2 percent. ^[2]
• Acute liver failure from paracetamol usually recovers fully if the patient survives without transplantation. ^[2]

• Acute liver failure
• Poisoning in children
• Self-harm and suicide risk assessment
• Chronic liver disease and analgesia
• Acetylcysteine and antidotes in overdose