Should N-acetylcysteine (NAC) be administered in cases of delayed paracetamol overdose with evidence of liver failure?

N-acetylcysteine (NAC) Administration in Delayed Paracetamol Overdose with Liver Failure

N-acetylcysteine (NAC) should still be administered in cases of delayed paracetamol overdose with evidence of liver failure, as it can improve survival outcomes even in patients with established hepatotoxicity. 1

Rationale for NAC in Established Liver Failure

NAC provides significant benefits in paracetamol-induced acute liver failure even when administered late:

• NAC significantly reduces mortality (0.7% vs 6%), progression to grade III-IV encephalopathy (51% vs 75%), and need for vasopressors (48% vs 80%) 1
• Meta-analysis shows NAC improves overall survival (76% vs 59%), liver transplant-free survival (64% vs 26%), and post-transplant survival (85.7% vs 71.4%) 1
• Benefits appear most pronounced in patients with early-stage encephalopathy (grade I-II), but are still present in advanced cases 1

Administration Protocol for Delayed Presentation

For patients presenting with delayed paracetamol overdose and liver failure:

1. Initiate NAC immediately without waiting for serum paracetamol determinations 1

2. Standard IV regimen: Total dose of 300 mg/kg

   • Loading dose: 150 mg/kg over 15-60 minutes
   • First maintenance dose: 50 mg/kg over 4 hours
   • Second maintenance dose: 100 mg/kg over 16 hours 1, 2

3. Continue NAC beyond the standard protocol if:

   • Elevated liver enzymes persist
   • INR >2.0
   • Patient remains clinically unstable 1

Monitoring During NAC Treatment

• Watch for hypersensitivity reactions (10-15% of patients), which can be managed with antihistamines and epinephrine if necessary 1
• Monitor liver function tests, coagulation parameters, and acid-base status regularly
• Note that hepatic impairment increases NAC exposure (1.6-fold) and half-life (80% increase), but dose adjustment is not considered clinically necessary 2

Supportive Care Measures

Concurrent supportive care is essential:

• Fluid resuscitation with isotonic crystalloids (0.9% NaCl) at 15-20 ml/kg/hr initially 1
• Correct electrolyte abnormalities, particularly phosphate and magnesium 1
• Consider sodium bicarbonate for severe metabolic acidosis (pH < 7.1) with hemodynamic instability 1
• Initiate early enteral nutrition if not contraindicated 1
• Consider renal replacement therapy for severe acidosis with altered mental status 1

Important Caveats

• The efficacy of NAC decreases with time from ingestion, but it still provides benefit regardless of delay 3
• Early discussion with a liver transplant unit is recommended if there is evidence of liver failure 3
• Higher plasma paracetamol concentrations at presentation correlate with increased risk of liver injury despite NAC treatment, suggesting standard dosing may be insufficient in severe cases 4
• Patient-tailored protocols with extended duration of NAC may be necessary for patients with established hepatotoxicity 5