What is the treatment for a patient with paracetamol (acetaminophen) poisoning, considering factors such as weight, time of ingestion, and pre-existing liver disease?

Treatment of Paracetamol (Acetaminophen) Poisoning

Administer N-acetylcysteine (NAC) immediately to all patients with suspected or confirmed paracetamol overdose when levels plot above the treatment line on the Rumack-Matthew nomogram, when timing is unknown with detectable levels, or when hepatotoxicity is already present—ideally within 8 hours of ingestion to maximize survival and prevent liver failure. 1

Immediate Assessment and Risk Stratification

Timing-Based Decision Algorithm

For patients presenting <4 hours post-ingestion:

• Administer activated charcoal 1 g/kg orally immediately, just prior to starting NAC 1, 2
• Obtain paracetamol level at 4 hours post-ingestion (levels drawn before 4 hours are unreliable and must be repeated) 1
• Use the Rumack-Matthew nomogram to determine treatment need once the 4-hour level is available 1, 2

For patients presenting 4-8 hours post-ingestion:

• Obtain paracetamol level immediately 1
• Plot on Rumack-Matthew nomogram: levels ≥200 mcg/mL at 4 hours or ≥50 mcg/mL at 12 hours indicate hepatotoxicity risk 3
• Start NAC immediately if above treatment line—this is the critical window where treatment within 8 hours results in only 2.9% developing severe hepatotoxicity 1

For patients presenting 8-24 hours post-ingestion:

• Start NAC loading dose immediately without waiting for laboratory results 1, 2
• Obtain paracetamol level and liver function tests (AST, ALT, INR) to guide continued treatment 1
• Efficacy diminishes after 8 hours: severe hepatotoxicity develops in 6.1% when treated within 10 hours versus 26.4% when treated after 10 hours 1

For patients presenting >24 hours post-ingestion:

• Start NAC immediately—the nomogram does NOT apply to late presentations 1
• Base treatment decisions on paracetamol levels, liver function tests, and clinical presentation rather than nomogram placement 1
• NAC remains beneficial even beyond 24 hours, though significantly less effective than early treatment 1, 4

Unknown Time of Ingestion

• Administer NAC loading dose immediately 1, 2
• Obtain paracetamol level urgently to determine need for continued treatment 1
• If any detectable paracetamol level is present, continue full NAC course 1

N-Acetylcysteine (NAC) Treatment Protocol

Standard IV Dosing Regimen (Two-Bag Protocol - Preferred)

The two-bag regimen has similar efficacy but significantly fewer adverse reactions compared to the traditional three-bag regimen: 5

• Loading dose: 200 mg/kg in 5% dextrose over 4 hours 5
• Maintenance dose: 100 mg/kg over 16 hours 5
• Total treatment time: 20 hours 5

Alternative Three-Bag IV Regimen

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 1, 2
• Second dose: 50 mg/kg over 4 hours 1, 2
• Third dose: 100 mg/kg over 16 hours 1, 2
• Total treatment time: 21 hours 1, 2

Oral NAC Regimen

• Loading dose: 140 mg/kg by mouth or nasogastric tube diluted to 5% solution 1
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1
• The 72-hour oral regimen is as effective as the 20-hour IV regimen and may be superior when treatment is delayed 1

Important Dilution Requirements

NAC is hyperosmolar (2600 mOsmol/L) and must be diluted in sterile water, 0.45% sodium chloride, or 5% dextrose prior to IV administration 2

Special Clinical Scenarios Requiring Modified Management

Fulminant Hepatic Failure

Administer NAC to all patients with hepatic failure from paracetamol regardless of time since ingestion—this is a Level B recommendation with proven mortality benefit: 1

• NAC reduces mortality from 80% to 52% in fulminant hepatic failure 1
• NAC reduces cerebral edema from 68% to 40% 1
• NAC reduces need for inotropic support from 80% to 48% 1
• Early NAC treatment (<10 hours) in fulminant hepatic failure results in 100% survival 1
• Late NAC treatment (>10 hours) results in 37% mortality 1

Repeated Supratherapeutic Ingestions (RSTI)

The Rumack-Matthew nomogram does NOT apply to RSTI—use these criteria instead: 1, 2

• Treat with NAC if ≥10 g or 200 mg/kg (whichever is less) in any single 24-hour period 1
• Treat with NAC if ≥6 g or 150 mg/kg (whichever is less) per 24-hour period for ≥48 hours 1
• Treat with NAC if serum paracetamol ≥10 mg/mL OR if AST or ALT >50 IU/L 1

Extended-Release Paracetamol

• Serial paracetamol levels should be obtained at 4 hours and again 4-6 hours later, as late increases may occur at 14 hours or beyond 1
• All potentially toxic ingestions (≥10 g or ≥200 mg/kg, whichever is less) should receive a full NAC course 5
• Patients ingesting ≥30 g or ≥500 mg/kg should receive increased doses of NAC 5

Massive Overdoses

For paracetamol concentrations more than double the nomogram line, increase NAC dosing: 1, 5

• Standard NAC doses may be insufficient for massive ingestions 1
• Consider step-wise NAC dose increases for levels at the 300-, 450-, and 600-lines on the nomogram 1

High-Risk Populations Requiring Lower Treatment Threshold

Chronic Alcohol Users

Treat with NAC even with levels in the "non-toxic" range on the nomogram: 1

• Severe hepatotoxicity documented with doses as low as 4-5 g/day in chronic alcohol users 1, 3
• Multiple case series show 20-33% mortality in chronic alcoholics taking 2.5-16.5 g/day (median 6.4 g/day) 3
• Depleted glutathione stores make these patients more vulnerable even at therapeutic doses 3

Pre-Existing Liver Disease

Paracetamol is NOT contraindicated in chronic liver disease, but dose reduction is essential: 3

• Maximum daily dose should be limited to 2-3 grams in patients with chronic liver disease or cirrhosis 3
• For malnourished patients with liver disease, stay at the lower end (2 grams/day) 3
• The only true contraindication is acute liver failure caused by paracetamol overdose itself 3

Patients on Enzyme-Inducing Drugs

• Lower threshold for NAC treatment if taking medications that induce cytochrome P-450 1
• Treat if serum paracetamol ≥10 mg/mL or if AST or ALT >50 IU/L 1

Criteria for Discontinuing NAC

NAC can be discontinued when ALL of the following criteria are met: 1

• Paracetamol level is undetectable 1
• AST and ALT are normal (no elevation above normal) 1
• INR is normal 1
• Patient is clinically well without signs of hepatotoxicity 1

Scenarios Mandating Extended NAC Treatment

Continue NAC beyond standard protocol in these situations: 1

• Delayed presentation (>24 hours post-ingestion) 1
• Extended-release paracetamol formulations 1
• Repeated supratherapeutic ingestions 1
• Unknown time of ingestion with detectable paracetamol levels 1
• Any elevation in AST or ALT above normal 1
• Rising transaminases 1
• Any coagulopathy present 1
• Chronic alcohol use 1

Red Flags Requiring Immediate NAC Restart

If hepatotoxicity develops (AST/ALT >1000 IU/L), restart NAC immediately and continue until transaminases are declining and INR normalizes: 1

Critical Care Management for Severe Cases

Indications for ICU-Level Care

Patients with severe hepatotoxicity (AST >1000 IU/L) or coagulopathy require ICU admission and early transplant hepatology consultation: 1, 6

Monitoring for Complications

• Hepatic encephalopathy requiring early intubation 6
• Cerebral edema requiring neuroprotective measures and hypertonic saline 6
• Coagulopathy requiring fresh frozen plasma 7
• Renal failure requiring high-dose hemofiltration to reduce ammonia levels 6
• Metabolic derangements 1

Liver Transplant Evaluation

Contact a liver transplant center immediately when there is any evidence of liver failure: 1

• Very high aminotransferases (AST/ALT >3500 IU/L) are highly correlated with paracetamol poisoning 1, 8
• Transplant is reserved for patients unlikely to survive with medical treatment alone 6

Common Pitfalls and Critical Caveats

Diagnostic Pitfalls

• Low or absent paracetamol levels do NOT rule out paracetamol poisoning if ingestion was remote or occurred over several days 1, 3
• Patients may present with elevated transaminases despite being stratified as "no risk" on the nomogram due to inaccurate history or increased susceptibility 1
• Normal aminotransferases at initial presentation (especially if <12 hours post-ingestion) do not exclude risk of developing toxicity 8
• Even therapeutic doses of 4 g/day for 14 days can cause ALT elevations >3 times normal in 31-41% of healthy adults 1, 3

Treatment Pitfalls

• Never withhold NAC even in late presentations—it still provides benefit and reduces mortality regardless of time since ingestion 1, 4, 7
• The Rumack-Matthew nomogram does NOT apply to: repeated supratherapeutic ingestions, extended-release formulations, presentations >24 hours, or unknown timing 1, 2
• Gastric lavage carries serious adverse effects and is only justified in rare life-threatening cases where the drug is not adsorbed by activated charcoal 9
• Ipecac syrup should not be used under any circumstances 9

Hypersensitivity Reactions to NAC

• Observe patients during and after infusion for hypersensitivity reactions including hypotension, wheezing, shortness of breath, and bronchospasm 2
• Immediately discontinue infusion if serious reaction occurs and initiate appropriate treatment 2
• NAC infusion may be carefully restarted after treatment of hypersensitivity 2

Fluid Overload Risk

• Total volume administered should be reduced for patients weighing <40 kg and those requiring fluid restriction 2