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 paracetamol poisoning when the serum level plots 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 Initial Management (First 4 Hours)

Activated Charcoal Administration:

• Give activated charcoal 1 g/kg orally in a slurry if the patient presents within 4 hours of ingestion and can protect their airway 1, 2
• Administer just prior to starting NAC 1
• Most effective within 1-2 hours but retains benefit up to 4 hours post-ingestion 1
• In a simulated large overdose study, activated charcoal given at 1 hour reduced paracetamol absorption by 66%, while combination therapy with gastric lavage provided no additional benefit (48% reduction) 2
• Even when given 2 hours post-ingestion, activated charcoal still reduced absorption by 23% 2

Do NOT perform gastric lavage or induce vomiting with ipecac—these interventions carry serious risks and provide no proven benefit over activated charcoal alone 1, 3, 2

Risk Stratification and NAC Initiation

For Single Acute Ingestions with Known Timing:

• Obtain serum paracetamol level at least 4 hours post-ingestion (levels drawn before 4 hours are unreliable and must be repeated) 1, 4
• Plot the level on the Rumack-Matthew nomogram 1, 4
• Start NAC immediately if the level plots at or above the treatment line (200 mcg/mL at 4 hours or 50 mcg/mL at 12 hours) 1, 5

For Unknown Timing or Delayed Presentation:

• Start NAC immediately without waiting for laboratory confirmation 1
• Obtain paracetamol level and liver function tests (AST, ALT, INR) to guide continuation of therapy 1, 6
• The nomogram does NOT apply to patients presenting >24 hours after ingestion—base treatment decisions on paracetamol levels and liver enzymes 1

For Repeated Supratherapeutic Ingestions:

• The nomogram does NOT apply 1, 4
• Start NAC if: ≥10 g or 200 mg/kg (whichever is less) in any 24-hour period, OR ≥6 g or 150 mg/kg per day for ≥48 hours 1
• Start NAC if serum paracetamol ≥10 mg/mL OR if AST or ALT >50 IU/L 1

NAC Dosing Protocols

Intravenous Regimen (Preferred, FDA-Approved):

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes (or diluted to reduce osmolarity) 1, 4
• Second dose: 50 mg/kg over 4 hours 1, 4
• Third dose: 100 mg/kg over 16 hours 1, 4
• Total duration: 21 hours, total dose 300 mg/kg 4

Alternative Two-Bag Regimen (Reduced Adverse Reactions):

• 200 mg/kg over 4 hours, then 100 mg/kg over 16 hours 7
• This modified regimen shows similar efficacy with significantly fewer adverse reactions compared to the traditional three-bag protocol 7, 8

Oral Regimen (When IV Access Unavailable):

• Loading dose: 140 mg/kg orally or via nasogastric tube 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

Critical Timing Considerations

Treatment Efficacy by Time Window:

• 0-8 hours: Only 2.9% develop severe hepatotoxicity when NAC started within 8 hours 1, 5
• 8-10 hours: 6.1% develop severe hepatotoxicity 1, 5
• 10-24 hours: 26.4% develop severe hepatotoxicity 1, 5
• >24 hours: NAC remains beneficial and reduces mortality even with delayed treatment, though efficacy is significantly diminished 1, 8

The 8-hour window is critical—every hour of delay increases hepatotoxicity risk exponentially 1

Special Populations Requiring Modified Management

Patients with Pre-Existing Liver Disease or Chronic Alcohol Use:

• Treat with NAC even if levels fall in the "non-toxic" range on the nomogram 1, 5
• Severe hepatotoxicity documented with doses as low as 4-5 g/day in chronic alcohol users 1, 5
• Maximum safe daily dose in these patients is 2-3 grams 5
• Malnourished patients have depleted glutathione stores, making them more vulnerable even at therapeutic doses 5

Patients with Established Acute Liver Failure:

• Administer NAC immediately regardless of time since ingestion (Level B recommendation) 1
• NAC reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and 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) still reduces mortality to 37% compared to 80% untreated 1, 5
• Very high aminotransferases (AST/ALT >3,500 IU/L) are highly correlated with paracetamol poisoning even without clear overdose history 1, 6

Massive Overdoses (>30 g or >500 mg/kg):

• Increase NAC dosing beyond standard protocol 1, 7
• For levels more than double the nomogram line, use increased acetylcysteine doses 7

Extended-Release Formulations:

• Obtain serial paracetamol levels at 4 hours and again 4-6 hours later 1
• All potentially toxic ingestions (≥10 g or ≥200 mg/kg) should receive full NAC course 7
• Patients ingesting ≥30 g or ≥500 mg/kg require increased NAC doses 7

Pediatric Considerations:

• For children weighing <70 kg, a 7 g ingestion represents >100 mg/kg, placing them at higher risk 1
• Adjust NAC dosing by weight using the same mg/kg protocols 4
• For patients <40 kg, reduce total fluid volume to avoid fluid overload 4

Monitoring and Continuation Criteria

Laboratory Monitoring:

• Obtain baseline AST, ALT, INR, creatinine, and paracetamol level 1
• Repeat liver function tests every 12-24 hours during NAC therapy 1
• Monitor for rising transaminases indicating evolving hepatotoxicity 6

When to Stop NAC After 21 Hours:

• Paracetamol level is undetectable AND 1
• AST and ALT remain normal (no elevation above normal) AND 1
• INR is normal AND 1
• Patient is asymptomatic 1

When to Continue or Restart NAC:

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

If hepatotoxicity develops (AST/ALT >1,000 IU/L), continue NAC until transaminases are declining and INR normalizes 1

Management of NAC Adverse Reactions

Hypersensitivity Reactions (Occur in Minority of Patients):

• Manifestations include rash, urticaria, facial flushing, pruritus, wheezing, shortness of breath, bronchospasm, or hypotension 4
• Immediately discontinue infusion if serious reaction occurs 4
• Treat hypersensitivity with antihistamines and/or corticosteroids 4
• NAC may be carefully restarted after treatment of hypersensitivity 4
• The modified two-bag regimen with slower loading dose (200 mg/kg over 4 hours instead of 150 mg/kg over 15 minutes) significantly reduces adverse reactions 7, 8

Disposition and Transplant Evaluation

ICU-Level Care Required For:

• Severe hepatotoxicity (AST >1,000 IU/L) 1
• Any coagulopathy 1
• Hepatic encephalopathy 9
• Acute liver failure 9

Early Transplant Hepatology Consultation Indicated For:

• AST >1,000 IU/L 1
• INR >2.0 despite NAC 1
• Hepatic encephalopathy (any grade) 9
• Rising creatinine suggesting hepatorenal syndrome 9

Neuroprotective Measures for Hepatic Encephalopathy:

• Early intubation to protect airway 9
• Hypertonic saline to reduce intracranial hypertension risk 9
• High-dose hemofiltration to reduce ammonia levels 9

Critical Pitfalls to Avoid

• Never wait for paracetamol levels if presentation is >8 hours post-ingestion or timing is unknown—start NAC immediately 1
• Never rely on normal transaminases at initial presentation (<12 hours) to exclude toxicity—hepatotoxicity develops over subsequent hours 6
• Never stop NAC at 21 hours if any liver enzyme elevation exists, even if paracetamol is undetectable 1
• Never use the nomogram for repeated supratherapeutic ingestions or presentations >24 hours post-ingestion 1, 4
• Never withhold NAC in chronic alcoholics or patients with liver disease even if levels appear "non-toxic" 1, 5
• Low or absent paracetamol levels do NOT rule out paracetamol poisoning if ingestion was remote or occurred over several days 1, 5