How should I manage a patient with acetaminophen overdose, including indications for N‑acetylcysteine (NAC), dosing protocols (intravenous 21‑hour regimen or oral regimen), use of activated charcoal, and monitoring of hepatic and coagulation parameters?

Acetaminophen Overdose Management

Immediate Treatment Algorithm

Start N-acetylcysteine (NAC) immediately for any suspected acetaminophen overdose without waiting for laboratory confirmation—treatment delay directly correlates with mortality, and efficacy drops dramatically after 8 hours. 1, 2

First-Line Actions (Within Minutes of Presentation)

• Administer activated charcoal (1 g/kg orally) if the patient presents within 4 hours of ingestion, just prior to starting NAC, provided the airway is protected and the patient can swallow safely. 1, 2
• Start NAC immediately in any patient with suspected acetaminophen overdose—do not wait for acetaminophen levels or liver function tests. 1, 3
• Draw blood for acetaminophen level (if 4-24 hours post-ingestion), AST, ALT, INR, creatinine, and electrolytes. 3

NAC Dosing Protocols

Intravenous 21-Hour Regimen (Preferred)

The standard IV protocol is superior to oral NAC and consists of three sequential infusions: 1, 2

• Loading dose: 150 mg/kg IV in 5% dextrose over 15 minutes 1, 2
• Second dose: 50 mg/kg IV over 4 hours 1, 2
• Third dose: 100 mg/kg IV over 16 hours (total 21-hour protocol) 1, 2

Oral Regimen (Alternative)

• Loading dose: 140 mg/kg orally or via nasogastric tube, diluted to 5% solution 2, 3
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 2, 3
• If the patient vomits within 1 hour of oral administration, repeat that dose immediately. 3
• The 72-hour oral regimen may be superior when treatment is delayed beyond 10 hours. 4

Risk Stratification Using the Rumack-Matthew Nomogram

Plot the acetaminophen level on the nomogram ONLY if presentation is 4-24 hours post-ingestion and time of ingestion is known: 1, 2

• Treat with NAC if the level plots at or above the "possible toxicity" line (150 mcg/mL at 4 hours or 37.5 mcg/mL at 12 hours). 1, 2
• The nomogram does NOT apply to repeated supratherapeutic ingestions, extended-release formulations, or presentations >24 hours post-ingestion. 2

When the Nomogram Cannot Be Used

Start NAC immediately in these scenarios regardless of acetaminophen level: 1, 2

• Unknown or uncertain time of ingestion with detectable acetaminophen level 2
• Presentation >24 hours post-ingestion 2
• Extended-release acetaminophen formulation 2
• Repeated supratherapeutic ingestions (≥10 g or 200 mg/kg in 24 hours, or ≥6 g or 150 mg/kg per day for ≥48 hours) 2
• Any evidence of hepatotoxicity (AST or ALT >50 IU/L) with detectable acetaminophen 2

Critical Timing and Efficacy Data

The window for maximum NAC efficacy is narrow and time-dependent: 5, 1, 4

• 0-8 hours: Only 2.9% develop severe hepatotoxicity when NAC is started within 8 hours 5, 1, 4
• 8-10 hours: 6.1% develop severe hepatotoxicity 5, 4
• 10-24 hours: 26.4% develop severe hepatotoxicity 5, 4
• 16-24 hours (high-risk patients): 41% develop severe hepatotoxicity, but this is still lower than untreated controls (58%) 2
• No deaths occurred among patients treated within 16 hours in the largest prospective study. 4

High-Risk Populations Requiring Lower Treatment Threshold

Treat these patients with NAC even if acetaminophen levels fall in the "non-toxic" range on the nomogram: 1, 2

• Chronic alcohol users: Severe hepatotoxicity documented with doses as low as 4-5 g/day 2
• Pre-existing liver disease: Maximum safe daily dose is 2-3 grams (vs. 4 grams in healthy adults) 1
• Patients taking enzyme-inducing drugs (phenytoin, carbamazepine, rifampin) 2
• Malnourished patients or those with glutathione depletion 1

Extended NAC Treatment Criteria

Continue NAC beyond the standard 21-hour protocol if ANY of the following persist after completion: 1, 2

• Detectable acetaminophen level 1
• Rising AST or ALT 1
• Elevated INR 1
• Delayed presentation (>24 hours post-ingestion) 1, 2
• Massive overdose (>30 g or 500 mg/kg) 1
• Pre-existing liver disease 1
• Extended-release acetaminophen formulation 2

Monitoring Requirements

Monitor hepatic and renal function throughout the NAC infusion: 1, 3

• Check AST, ALT, INR, creatinine, and electrolytes at baseline 3
• Repeat labs after completion of the 21-hour NAC protocol 1
• If AST/ALT are rising or INR is elevated, continue NAC and repeat labs every 12-24 hours until transaminases are declining and INR normalizes. 1
• Monitor for complications of acute liver failure: encephalopathy, coagulopathy, renal failure, metabolic derangements. 1

Definition of Severe Hepatotoxicity and ICU Criteria

Severe hepatotoxicity is defined as AST or ALT >1,000 IU/L and mandates ICU admission: 1, 2

• Any coagulopathy (elevated INR) 1
• Encephalopathy 1
• Renal failure 1
• Metabolic derangements 1
• Early consultation with transplant hepatology is essential for any patient with severe hepatotoxicity or signs of liver failure. 1

Special Clinical Scenario: Fulminant Hepatic Failure

Administer NAC to all patients with fulminant hepatic failure from acetaminophen, regardless of time since ingestion (Level B recommendation): 2

• NAC reduces mortality from 80% to 52% in established liver failure 2
• NAC reduces cerebral edema from 68% to 40% 2
• NAC reduces need for inotropic support from 80% to 48% 2
• Early NAC treatment (<10 hours) in fulminant hepatic failure results in 100% survival without progression or dialysis. 2
• Late NAC treatment (>10 hours) still reduces mortality to 37% (vs. 80% untreated). 2

Common Pitfalls and How to Avoid Them

Do not wait for acetaminophen levels if presentation is delayed or timing is uncertain—start NAC immediately. 1, 2

• Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days. 2
• Patient-reported dose is often inaccurate—patients may underreport intake or be unreliable historians. 1
• Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with acetaminophen poisoning and should prompt NAC treatment even when history is lacking. 2

Do not stop NAC prematurely—verify all criteria are met before discontinuation: 2

• Acetaminophen level must be undetectable 2
• AST and ALT must be normal or declining 2
• INR must be normal 2
• If any of these criteria are not met, continue NAC until they normalize. 2

Do not rely solely on the nomogram for treatment decisions: 1, 2

• The nomogram underestimates risk for patients presenting within 8 hours of overdose. 2
• Patients may present with elevated transaminases despite being stratified as "no risk" due to inaccurate history or increased susceptibility. 2
• When in doubt, treat—NAC has minimal adverse effects (nausea, vomiting, rash <5%, bronchospasm 1-2%). 6

Adverse Effects of NAC

NAC is generally safe with minimal adverse effects: 6, 7

• Intravenous route: Anaphylactoid reactions (most common), cutaneous reactions, transient bronchospasm (1-2%) 7
• Oral route: Nausea, vomiting, intestinal upset 7
• No serious adverse events were rated by investigators in large prospective studies. 8

Disposition

Admit to ICU: 1

• Severe hepatotoxicity (AST >1,000 IU/L) 1
• Any coagulopathy, encephalopathy, renal failure, or metabolic derangements 1
• Pre-existing liver disease with any evidence of hepatotoxicity 1

Admit to monitored bed: 1

• All patients receiving NAC 1
• Patients with acetaminophen levels in the "possible" or "probable" risk zones on the nomogram 1