What is the management for paracetamol (Acetaminophen) poisoning?

Management of Paracetamol (Acetaminophen) Poisoning

Administer N-acetylcysteine (NAC) immediately to all patients with suspected or confirmed paracetamol overdose when serum levels plot above the "possible toxicity" line on the Rumack-Matthew nomogram, or when timing is uncertain, or when hepatotoxicity is already present—ideally within 8 hours of ingestion to maximize efficacy. 1, 2

Initial Assessment and Stabilization

Critical Historical Information

• Determine the exact time of ingestion, as this is essential for nomogram use and risk stratification, though reported quantities are often inaccurate and unreliable 1, 2
• Identify the formulation ingested: immediate-release versus extended-release paracetamol, as extended-release requires modified management due to prolonged absorption 1, 3
• Assess for high-risk factors including chronic alcohol use (≥3 drinks/day), malnutrition, concurrent use of CYP2E1-inducing drugs (isoniazid, phenytoin, carbamazepine), or pre-existing liver disease 1, 2

Immediate Interventions Within 4 Hours

• Administer activated charcoal (1 g/kg orally) just prior to starting NAC if the patient presents within 4 hours of ingestion and can protect their airway 1, 2
• Activated charcoal is most effective within 1-2 hours but may provide benefit up to 4 hours post-ingestion 1

Essential Laboratory Testing

• Draw serum paracetamol concentration at least 4 hours post-ingestion for acute overdose, as levels obtained earlier may be misleadingly low and not represent peak concentrations 1, 2
• Obtain baseline liver function tests: AST, ALT, alkaline phosphatase, total bilirubin 1, 4, 2
• Check coagulation status: prothrombin time/INR 1, 4, 2
• Assess renal function: creatinine, BUN 1, 2
• Monitor metabolic parameters: glucose, electrolytes, arterial lactate, arterial blood gas 1, 4

Risk Stratification Using the Rumack-Matthew Nomogram

When to Use the Nomogram

• Apply the nomogram ONLY for single acute ingestions with known time of ingestion when paracetamol level is drawn 4-24 hours post-ingestion 1, 2
• The nomogram does NOT apply to repeated supratherapeutic ingestions, unknown time of ingestion, presentations >24 hours post-ingestion, or extended-release formulations 1, 3

Treatment Thresholds

• Initiate NAC if paracetamol concentration plots at or above the "possible toxicity" line (the lower treatment line at 150 mg/L at 4 hours, declining to 18.8 mg/L at 24 hours) 1, 2
• The nomogram may underestimate risk in high-risk populations (chronic alcoholics, malnourished patients, those on enzyme-inducing drugs), and these patients should be treated even with levels in the "non-toxic" range 1, 5, 2

Special Considerations for Extended-Release Formulations

• If the 4-hour level is below the treatment line, obtain a second level at 8-10 hours post-ingestion, as delayed absorption may cause a later peak 1, 2, 3
• Treat all potentially toxic modified-release ingestions (≥10 g or ≥200 mg/kg, whichever is less) with a full course of NAC 3

N-Acetylcysteine (NAC) Treatment Protocol

Standard Intravenous Regimen (21-Hour Protocol)

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

Alternative Two-Bag Regimen (20-Hour Protocol)

• First infusion: 200 mg/kg over 4 hours 3
• Second infusion: 100 mg/kg over 16 hours 3
• This regimen has similar efficacy but significantly reduced adverse reactions compared to the three-bag regimen 3

Oral NAC Regimen (72-Hour Protocol)

• 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

Timing and Efficacy

• NAC within 8 hours: 2.9% risk of severe hepatotoxicity 1, 5
• NAC within 10 hours: 6.1% risk of severe hepatotoxicity 1, 5
• NAC after 10 hours: 26.4% risk of severe hepatotoxicity 1, 5
• NAC between 16-24 hours: 41% hepatotoxicity rate in high-risk patients (still better than 58% in untreated historical controls) 1
• Treatment after 15 hours yields limited efficacy but should never be withheld, as it still provides benefit and does not worsen outcomes 2, 6

Special Clinical Scenarios Requiring Immediate NAC

Unknown Time of Ingestion

• Administer NAC loading dose immediately without waiting for laboratory confirmation if time of ingestion is unknown and paracetamol level is detectable 1, 2
• Continue full 21-hour protocol regardless of subsequent levels if timing cannot be established 1

Delayed Presentation (>24 Hours Post-Ingestion)

• Start NAC immediately based on clinical presentation and laboratory findings rather than nomogram placement 1, 2
• Treatment decisions should be guided by paracetamol levels (if detectable), AST/ALT elevations, and INR 1
• Even late NAC administration reduces mortality and complications in established hepatotoxicity 1, 6

Fulminant Hepatic Failure

• Administer NAC to ALL patients with hepatic failure thought to be due to paracetamol, regardless of time since ingestion (Level B recommendation) 1, 5
• NAC reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and need for inotropic support from 80% to 48% 1, 5
• Early NAC (<10 hours) in fulminant hepatic failure results in 100% survival without progression or dialysis 1, 5
• Late NAC (>10 hours) in fulminant hepatic failure results in 37% mortality and 51% requiring dialysis 1, 5

Repeated Supratherapeutic Ingestions (RSTI)

• Treat with NAC if serum paracetamol ≥10 mg/mL OR if AST or ALT >50 IU/L 1
• Treat if ≥10 g or 200 mg/kg (whichever is less) during a single 24-hour period 1
• Treat if ≥6 g or 150 mg/kg (whichever is less) per 24-hour period for ≥48 hours 1
• Chronic alcoholics can develop severe hepatotoxicity with doses as low as 4-5 g/day 1, 5, 4

Massive Overdoses

• For paracetamol concentrations more than double the nomogram line, increase NAC dosing 1, 3
• For ingestions ≥30 g or ≥500 mg/kg, administer increased doses of NAC 3

Cirrhotic Patients

• Administer NAC immediately to all cirrhotic patients with suspected or confirmed paracetamol overdose, as they have increased susceptibility even at therapeutic doses 5
• Use a lower treatment threshold, as the nomogram may underestimate risk in cirrhotic patients 5
• Continue NAC beyond 21 hours if AST/ALT remains elevated or rising, INR remains elevated, or detectable paracetamol persists 5

Criteria for Discontinuing NAC

Standard Stopping Criteria (Low-Risk Patients)

• NAC can be discontinued when ALL of the following are met: 1
  • Paracetamol level is undetectable
  • AST and ALT are normal (not just "improving")
  • INR is normal
  • Patient is asymptomatic

Scenarios Requiring Extended NAC Beyond 21 Hours

• Continue NAC if any of the following are present: 1, 5
  • AST or ALT remains elevated or rising
  • INR remains elevated
  • Detectable paracetamol level persists
  • Delayed presentation (>24 hours post-ingestion)
  • Extended-release formulation
  • Repeated supratherapeutic ingestions
  • Unknown time of ingestion with detectable levels
  • Chronic alcohol use or other high-risk factors

Critical Red Flags Mandating Continuation or Restart of NAC

• Do not stop or immediately restart NAC if: 1
  • Any elevation in AST or ALT above normal
  • Rising transaminases
  • Any coagulopathy (elevated INR)
  • Detectable paracetamol level
  • Clinical signs of hepatotoxicity (jaundice, right upper quadrant tenderness, altered mental status)

Monitoring During Treatment

Serial Laboratory Assessment

• Repeat AST, ALT, INR, and paracetamol level at 12-24 hours to assess for evolving hepatotoxicity 1, 4
• Monitor for hepatotoxicity markers: AST/ALT >1,000 IU/L indicates significant liver injury; levels >3,500 IU/L are highly correlated with paracetamol poisoning 1, 4
• Watch for coagulopathy development (elevated INR/PT) as a marker of synthetic liver dysfunction 1, 4

Clinical Monitoring for Complications

• Assess for hepatic encephalopathy: altered mental status, confusion, asterixis 1, 4
• Monitor for hypoglycemia, which indicates severe hepatic dysfunction 1, 4
• Check for renal dysfunction: rising creatinine, oliguria 1, 4
• Measure arterial lactate: elevated lactate predicts poor prognosis 1, 4

Adverse Reactions to NAC

• Anaphylactoid reactions occur in up to 15% of patients, particularly during the loading dose when concentrations are highest 1, 7, 8
• Symptoms include hypotension, wheezing, shortness of breath, bronchospasm, urticaria, and flushing 2
• Temporarily stop the infusion if anaphylactoid reaction occurs, treat with antihistamines ± bronchodilators, then restart at a slower rate 1
• The two-bag regimen significantly reduces anaphylactoid reactions (odds ratio 0.23) and vomiting (odds ratio 0.37) compared to the traditional three-bag regimen 8

Disposition and Consultation

ICU-Level Care Indications

• Transfer to ICU if: 1
  • AST/ALT >1,000 IU/L (severe hepatotoxicity)
  • Any coagulopathy (INR >1.5)
  • Hepatic encephalopathy
  • Renal dysfunction
  • Metabolic acidosis or elevated lactate

Transplant Hepatology Consultation

• Contact liver transplant center immediately for any evidence of liver failure, as early consultation improves outcomes 1
• Patients with severe hepatotoxicity or coagulopathy require early transplant hepatology evaluation 1

Common Pitfalls and Caveats

Pitfall #1: Relying on Patient-Reported Dose

• The reported quantity of paracetamol ingested is often inaccurate and should not guide treatment decisions alone 2
• Always obtain objective paracetamol levels and treat based on laboratory findings 2

Pitfall #2: Drawing Paracetamol Level Too Early

• Levels obtained <4 hours post-ingestion may be misleadingly low and not represent peak concentrations 1, 2
• If level is drawn early, repeat at 4 hours or start NAC empirically 1

Pitfall #3: Misapplying the Nomogram

• The nomogram ONLY applies to single acute ingestions with known timing 1, 2
• Do not use the nomogram for RSTI, unknown timing, >24-hour presentations, or extended-release formulations 1, 3

Pitfall #4: Stopping NAC Prematurely

• NAC should not be stopped simply because 21 hours have elapsed 1
• Continue NAC until ALL stopping criteria are met (undetectable paracetamol, normal transaminases, normal INR) 1

Pitfall #5: Underestimating Risk in High-Risk Populations

• Chronic alcoholics, malnourished patients, and those on enzyme-inducing drugs can develop severe hepatotoxicity with "non-toxic" levels 1, 5, 2
• Use a lower treatment threshold in these populations 1, 5

Pitfall #6: Delaying Treatment While Awaiting Levels

• If paracetamol level cannot be obtained within 8 hours of ingestion, or if there is clinical evidence of toxicity, start NAC immediately without waiting 2
• Treatment should never be delayed for laboratory confirmation when clinical suspicion is high 1, 2

Pitfall #7: Dismissing Low or Undetectable Levels in Late Presentations

• Low or absent paracetamol levels do NOT rule out paracetamol poisoning if ingestion was remote or occurred over several days 1
• In late presentations, treatment decisions should be based on transaminase elevations and clinical presentation rather than paracetamol levels alone 1