What is the management of acetaminophen (N-acetyl-p-aminophenol) overdose?

Management of Acetaminophen Overdose

Administer N-acetylcysteine (NAC) immediately for any suspected or confirmed acetaminophen overdose when serum levels plot above the treatment line on the Rumack-Matthew nomogram, when time of ingestion is unknown, or when hepatotoxicity is already present—ideally within 8 hours of ingestion to maximize efficacy. 1, 2

Initial Assessment and Decontamination

Activated charcoal (1 g/kg orally) should be given just prior to starting NAC if the patient presents within 4 hours of ingestion. 1, 2 Do not delay NAC administration even if activated charcoal has been given. 1

Obtain acetaminophen level as early as possible, but no sooner than 4 hours post-ingestion, as earlier levels cannot be reliably interpreted. 3 If an assay cannot be obtained, assume the overdose is potentially toxic and treat accordingly. 3

Obtain baseline liver function tests (AST, ALT) and prothrombin time to assess for developing hepatotoxicity. 2

Risk Stratification Using the Rumack-Matthew Nomogram

The nomogram applies ONLY to single acute ingestions with known time of ingestion, measured between 4-24 hours post-ingestion. 2, 3

• Plot the acetaminophen concentration against time post-ingestion 2
• Values above the treatment line (200 mcg/mL at 4 hours, connecting to 50 mcg/mL at 12 hours) indicate need for NAC 3
• A conservative line 25% below this defines minimal risk 3

The nomogram CANNOT be used for: 2

• Presentations >24 hours post-ingestion
• Extended-release acetaminophen
• Repeated supratherapeutic ingestions
• Unknown time of ingestion

NAC Administration: Timing is Critical

Optimal Window (0-8 hours)

NAC initiated within 8 hours results in only 2.9% risk of severe hepatotoxicity. 2, 4 There is no difference in outcome whether NAC is started 0-4 hours versus 4-8 hours after ingestion. 4

Acceptable Window (8-10 hours)

Severe hepatotoxicity develops in 6.1% when NAC is started within 10 hours. 2, 4

Delayed Window (10-24 hours)

Severe hepatotoxicity develops in 26.4% when treatment begins 10-24 hours post-ingestion. 2, 4 Among high-risk patients treated 16-24 hours after ingestion, hepatotoxicity occurs in 41%—still lower than untreated historical controls (58%). 2

Beyond 24 Hours

NAC should still be administered to patients presenting >24 hours after ingestion, as it remains beneficial in reducing hepatotoxicity and mortality even with delayed treatment. 2 Treatment decisions must be based on acetaminophen levels, liver function tests, and clinical presentation rather than nomogram placement. 2

NAC Dosing Regimens

Intravenous Protocol (21-hour 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

Oral Protocol (72-hour regimen)

• Loading dose: 140 mg/kg by mouth or nasogastric tube, diluted to 5% solution 1, 2
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses 1, 2

The 72-hour oral regimen is as effective as the 20-hour IV regimen and may be superior when treatment is delayed. 4

Special Clinical Scenarios Requiring Immediate NAC

Administer NAC in the following situations regardless of nomogram placement or acetaminophen levels: 1, 2

• Acute liver failure where acetaminophen ingestion is suspected or possible, even without confirmatory history 1, 2
• Very high aminotransferases (AST/ALT >3,500 IU/L), which are highly correlated with acetaminophen poisoning 2
• Detectable acetaminophen levels with unknown time of ingestion 2
• Extended-release acetaminophen overdose 1, 2
• Repeated supratherapeutic ingestions (>4g per 24 hours) with serum acetaminophen ≥10 mg/mL or elevated aminotransferases (AST or ALT >50 IU/L) 2

High-Risk Populations Requiring Lower Treatment Threshold

Patients with chronic alcohol consumption should be treated with NAC even with levels in the "non-toxic" range, as severe hepatotoxicity has been documented with doses as low as 4-5 g/day. 2 Fasting patients and those with malnutrition are also at increased risk. 1

Criteria for Discontinuing NAC

NAC can be discontinued when: 2

• Acetaminophen level is undetectable AND
• Liver function tests remain normal (no elevation in AST or ALT above normal) AND
• No coagulopathy present

NAC must be continued or restarted immediately if: 2

• Any elevation in AST or ALT above normal
• Rising transaminases
• Any coagulopathy develops
• Detectable acetaminophen level persists
• Clinical signs of hepatotoxicity

Extended Treatment Scenarios

Certain situations mandate longer NAC courses despite undetectable acetaminophen: 2

• Delayed presentation (>24 hours post-ingestion)
• Extended-release acetaminophen
• Repeated supratherapeutic ingestions
• Unknown time of ingestion
• Chronic alcohol use

Management of Established Hepatotoxicity

For patients with fulminant hepatic failure from acetaminophen, NAC must be administered regardless of time since ingestion. 2 NAC reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48%. 2

Early NAC treatment (<10 hours) in fulminant hepatic failure results in 100% survival. 2 Late NAC treatment (>10 hours) results in 37% mortality. 2

If hepatotoxicity develops (AST/ALT >1000 IU/L), NAC should be continued until transaminases are declining and INR normalizes. 2

Supportive Care

• Maintain fluid and electrolyte balance based on clinical evaluation 3
• Treat hypoglycemia as necessary 3
• Administer vitamin K1 if prothrombin time ratio exceeds 1.5 3
• Give fresh frozen plasma if prothrombin time ratio exceeds 3.0 3
• Avoid diuretics and forced diuresis 3

Disposition

Patients with severe hepatotoxicity (AST >1000 IU/L) or coagulopathy require ICU-level care and early consultation with transplant hepatology. 2

Common Pitfalls

• Do not wait for acetaminophen levels to start NAC if there is strong suspicion of significant overdose 1, 3
• Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days 2
• Patients may present with elevated transaminases despite "no risk" nomogram placement due to inaccurate history or increased susceptibility 2
• Severe and persistent vomiting may occur; dilution of oral NAC minimizes this propensity 3
• Anaphylactoid reactions are the most frequent adverse events with IV NAC, usually occurring during loading doses; treat by discontinuing infusion, administering antihistamines, then restarting at a slower rate 5, 6