Treatment of Paracetamol (Acetaminophen) Poisoning
Immediately administer N-acetylcysteine (NAC) to any patient with suspected or confirmed paracetamol overdose when serum levels plot above the "possible toxicity" 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 Risk Stratification
Immediate Actions Upon Presentation
Obtain acetaminophen serum concentration at least 4 hours post-ingestion, as levels drawn earlier may be misleading and not represent peak concentrations 1, 2
Administer activated charcoal (1 g/kg orally) just prior to starting NAC if the patient presents within 4 hours of ingestion, as this reduces absorption and is most effective within 1-2 hours but may provide benefit up to 4 hours 1, 2
Obtain baseline laboratory tests immediately: AST, ALT, bilirubin, INR, creatinine, BUN, blood glucose, and electrolytes to monitor hepatic and renal function 1, 2
Using the Rumack-Matthew Nomogram
The nomogram applies ONLY to acute single ingestions with known timing between 4-24 hours post-ingestion—it does NOT apply to repeated supratherapeutic ingestions, extended-release formulations, or presentations >24 hours 1, 2
Plot the acetaminophen concentration against time post-ingestion: if the level is at or above the "possible toxicity" line (the lower dotted line), immediately start NAC 1, 2
For extended-release acetaminophen overdoses: if the 4-hour level is below the possible toxicity line, obtain a second sample at 8-10 hours post-ingestion, as absorption is prolonged 1, 2
NAC Treatment Protocol
Standard IV Dosing Regimen (21-Hour Protocol)
Third dose: 100 mg/kg over 16 hours (total 300 mg/kg over 21 hours) 1, 2
NAC must be diluted prior to IV administration as it is hyperosmolar (2600 mOsmol/L); use sterile water, 0.45% sodium chloride, or 5% dextrose 2
Alternative Oral Dosing Regimen (72-Hour Protocol)
Loading dose: 140 mg/kg orally or via nasogastric tube, diluted to 5% solution 1
Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 1
Two-Bag Regimen (Newer Alternative)
- 200 mg/kg over 4 hours, then 100 mg/kg over 16 hours—this regimen has similar efficacy but significantly reduced adverse reactions compared to the three-bag regimen 3
Critical Time-Based Treatment Windows
0-8 Hours Post-Ingestion (Optimal Window)
NAC initiated within 8 hours results in only 2.9% risk of severe hepatotoxicity—this is the critical window for maximal hepatoprotection 1
Start NAC immediately without waiting for laboratory confirmation if clinical suspicion is high 1, 2
8-10 Hours Post-Ingestion (Diminishing Efficacy)
- Efficacy begins to decline: severe hepatotoxicity develops in 6.1% when NAC is started within 10 hours 1
10-24 Hours Post-Ingestion (Late but Still Beneficial)
Severe hepatotoxicity develops in 26.4% when treatment begins in this window, compared to 58% in untreated historical controls 1
Among high-risk patients treated 16-24 hours after ingestion, hepatotoxicity still develops in 41%—but this remains significantly lower than untreated patients 1
>24 Hours Post-Ingestion (Very Late Presentation)
NAC should still be administered immediately, as it remains beneficial in reducing hepatotoxicity and mortality even with delayed treatment 1
The Rumack-Matthew nomogram does NOT apply—treatment decisions must be based on acetaminophen levels, liver function tests, and clinical presentation 1
Administer NAC without waiting for laboratory confirmation when patients present beyond 24 hours 1
Special Clinical Scenarios Requiring Immediate NAC
Unknown Time of Ingestion
Administer loading dose of NAC immediately, then obtain acetaminophen concentration to determine need for continued treatment 1, 2
If acetaminophen level is detectable, continue full NAC course 1
Established Hepatic Failure
Administer NAC to all patients with hepatic failure thought to be due to acetaminophen, regardless of time since ingestion (Level B recommendation) 1, 2
NAC reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48% in fulminant hepatic failure 1
Early NAC treatment (<10 hours) in fulminant hepatic failure results in 100% survival without progression or dialysis 1
Late NAC treatment (>10 hours) in fulminant hepatic failure results in 37% mortality and 51% requiring dialysis 1
Hepatotoxicity with Suspected Overdose
Patients with elevated transaminases (AST or ALT >50 IU/L) and suspected or known acetaminophen overdose should receive NAC, including repeated supratherapeutic ingestions 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 1
Repeated Supratherapeutic Ingestions
NAC should be considered if serum acetaminophen concentration is ≥10 mg/mL or if aminotransferases are elevated (AST or ALT >50 IU/L) 1
The Rumack-Matthew nomogram does NOT apply to repeated supratherapeutic ingestions—obtain acetaminophen concentration and liver function tests to guide treatment 1, 2
Massive Overdoses
Massive paracetamol overdoses resulting in concentrations more than double the nomogram line should be managed with increased doses of acetylcysteine 3
Patients ingesting ≥30 g or ≥500 mg/kg should receive increased doses of acetylcysteine 3
Modified-Release Formulations
All potentially toxic modified-release paracetamol ingestions (≥10 g or ≥200 mg/kg, whichever is less) should receive a full course of acetylcysteine 3
Extended-release acetaminophen overdose requires individualized treatment due to prolonged absorption 1
High-Risk Populations Requiring Lower Treatment Threshold
Chronic Alcohol Consumption
Patients with chronic alcohol use 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 1
The nomogram may underestimate hepatotoxicity risk in patients with chronic alcoholism—consider treating even if acetaminophen concentrations are in the nontoxic range 2
Other Risk Factors
Patients with malnutrition or taking CYP2E1 enzyme-inducing drugs (e.g., isoniazid) should have a lower threshold for treatment 2, 4
For patients weighing less than 70 kg, a 7g ingestion represents >100 mg/kg, placing them at higher risk 1
Discontinuing NAC Therapy
Laboratory Criteria for Stopping NAC
NAC can be discontinued when acetaminophen level is undetectable AND liver function tests remain normal (no elevation in AST or ALT above normal) 1
If criteria are met at 12 hours, a 12-hour NAC course may be safe in carefully selected low-risk patients with normal labs at presentation and 12 hours 1
Scenarios Requiring Extended Treatment
- Continue NAC beyond 21 hours for: delayed presentation (>24 hours post-ingestion), extended-release acetaminophen, repeated supratherapeutic ingestions, unknown time of ingestion, or chronic alcohol use 1
Red Flags Mandating Continuation or Restart of NAC
Do NOT stop NAC or restart immediately if: any elevation in AST or ALT above normal, rising transaminases, any coagulopathy, detectable acetaminophen level, or clinical signs of hepatotoxicity 1
If hepatotoxicity develops (AST/ALT >1000 IU/L), restart NAC immediately and continue until transaminases are declining and INR normalizes 1
Disposition and Monitoring
ICU-Level Care Indications
- Patients with severe hepatotoxicity (AST >1000 IU/L) or coagulopathy require ICU-level care and early consultation with transplant hepatology 1
Ongoing Monitoring
- Monitor liver function tests (AST, ALT, bilirubin), coagulation parameters (INR, PT), renal function (creatinine, BUN), and electrolytes throughout treatment 1, 2
Critical Pitfalls and Caveats
Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days 1
Patients may present with elevated transaminases despite being stratified as "no risk" on the nomogram due to inaccurate history or increased susceptibility 1
The reported history of quantity ingested is often inaccurate and is not a reliable guide to therapy—rely on serum levels and clinical presentation 2
Acetaminophen concentrations obtained earlier than 4 hours post-ingestion may be misleading 2
Mortality risk correlates with treatment delay—both deaths in landmark studies occurred in patients with substantial treatment delays (17.8 and 24 hours post-ingestion) 1
Delaying NAC administration while awaiting laboratory confirmation can reduce its efficacy—treat promptly when overdose is suspected 5
Adverse Effects of NAC
Monitor for hypersensitivity reactions including hypotension, wheezing, shortness of breath, and bronchospasm—observe patients during and after infusion 2
If a serious reaction occurs, immediately discontinue infusion and initiate appropriate treatment; NAC may be carefully restarted after treatment of hypersensitivity 2
Common adverse reactions (>2%) include rash, urticaria/facial flushing, pruritus, nausea, vomiting, and diarrhea 5, 2
Anaphylactoid reactions occur particularly early during IV administration when concentrations are highest—newer regimens with slower initial infusion rates have reduced incidence 6
Fluid Management Considerations
- Total volume administered should be reduced for patients weighing less than 40 kg and for those requiring fluid restriction to avoid fluid overload 2