Makindo Medical Notes

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Deaths or episodes of acute liver failure in patients who start treatment within 8 hours of a single acute overdose are extremely rare due to the availability of a highly effective antidote, acetylcysteine (NAC).

About

• A potentially fatal overdose, especially if treatment is delayed or not provided.
• The minimum lethal dose is typically 12-15 g (24-30 x 500 mg tablets), though some individuals, especially those with risk factors such as chronic alcohol use or malnutrition, may be more susceptible to lower doses.
• It's important to determine both the time of ingestion and the amount taken to guide management.
• Paracetamol toxicity is one of the most common causes of acute liver failure globally, and it accounts for a significant proportion of overdoses in emergency departments.

Metabolism: Toxicity from NAPQI

• Paracetamol is primarily metabolized in the liver by conjugation with glucuronide and sulfate. However, a small fraction is converted to N-acetyl-p-benzoquinone imine (NAPQI), a toxic metabolite.
• Under normal circumstances, NAPQI is detoxified by glutathione and excreted. In an overdose, glutathione stores become depleted, allowing NAPQI to accumulate.
• NAPQI binds to hepatocytes, causing oxidative damage, cell death, and liver necrosis. If untreated, this can progress to fulminant hepatic failure.

Risk Factors for Increased Toxicity

• Chronic alcohol use: Chronic alcoholics may have increased CYP2E1 activity, which enhances NAPQI formation, and they may have depleted glutathione stores.
• Malnutrition: Patients with poor nutritional status or chronic illness may have low baseline glutathione levels, increasing susceptibility to toxicity.
• Pre-existing liver disease: Underlying liver dysfunction can exacerbate paracetamol toxicity, even with lower doses.

Clinical Features

• Symptoms typically develop in four stages after ingestion:
  • Phase 1 (0-24 hours): Non-specific symptoms such as nausea, vomiting, diaphoresis, and malaise. Many patients may remain asymptomatic during this phase.
  • Phase 2 (24-72 hours): Onset of right upper quadrant pain, elevated liver enzymes (AST/ALT), and potential liver enlargement. Symptoms of hepatic injury may begin to manifest.
  • Phase 3 (72-96 hours): Hepatic failure, jaundice, encephalopathy, coagulopathy, hypoglycemia, and lactic acidosis. This is the most critical phase, where complications such as cerebral edema and multi-organ failure may develop.
  • Phase 4 (4-14 days): Recovery phase if the patient survives, marked by resolution of hepatic dysfunction. In severe cases, patients may require a liver transplant.
• Late signs of toxicity include hypoglycemia, bleeding, jaundice, and encephalopathy.
• Unusual symptoms like a new distaste for cigarettes can suggest liver injury.

Investigations

• Paracetamol levels: Should be checked 4 hours post-ingestion or later, and plotted on a treatment nomogram to assess the need for NAC therapy.
• Liver function tests (LFTs): AST, ALT, and bilirubin levels are critical to assess liver damage.
• Prothrombin time (PT)/INR: Elevated levels indicate impaired liver synthetic function and are important prognostic indicators.
• Venous blood gas (VBG): Helps assess for metabolic acidosis, which is a poor prognostic sign.
• Other blood tests: Full blood count (FBC), U&E, and salicylate levels to rule out co-ingestion or other toxicities.

Management: When to Start NAC (N-Acetylcysteine)

• NAC indications: NAC is highly effective in preventing liver damage when given within 8 hours of overdose.
  • Plasma paracetamol concentration above the treatment line on the paracetamol nomogram.
  • Patients presenting within 8 hours of ingestion of more than 150 mg/kg if there is a delay in obtaining paracetamol levels.
  • Patients presenting 8-24 hours after ingestion of more than 150 mg/kg, even if levels are not yet available.
  • Patients presenting more than 24 hours after overdose with signs of liver damage, such as jaundice, elevated ALT, INR >1.3, or detectable paracetamol concentration.
• NAC can prevent hepatic damage even in patients who present late with evidence of liver injury if started promptly.

Management: When to Administer Activated Charcoal

• Activated charcoal (50 g in 300 mL water) should be administered orally if the patient presents within 1 hour of ingestion and has ingested more than 150 mg/kg of paracetamol.
• Charcoal binds the drug in the gastrointestinal tract, reducing absorption and lowering plasma concentrations.

Treatment Line: All patients with paracetamol levels above the treatment line should receive NAC.

Administering NAC

Use a ceiling weight of 110 kg when calculating NAC doses in obese patients. NAC is nearly 100% effective in preventing liver damage if given within 8 hours of overdose.

• Bag 1: 150 mg/kg in 200 mL of 5% dextrose (D5W) or normal saline (NS) over 1 hour.
• Bag 2: 50 mg/kg in 500 mL of 5% D5W or NS over 4 hours.
• Bag 3: 100 mg/kg in 1 L of 5% D5W or NS over 16 hours.
• Bag 4 (Optional): A fourth bag (same as Bag 3) may be given if the following occur:
  • Serum creatinine elevated above baseline.
  • ALT elevated more than 2 times baseline.
  • INR >1.3 or a rise in INR of >0.2.

Side Effects of NAC

• Allergic reactions, including rash and flushing, are common.
• Bronchospasm is rare but can occur. Slow the infusion rate and monitor closely.
• Ensure access to resuscitation equipment during administration, especially in patients with a history of asthma or allergies.

Monitoring

• Frequent monitoring of NEWS (National Early Warning Score), liver function (ALT/AST), and coagulation (prothrombin time/INR) is necessary.
• Regular checks of serum creatinine and electrolyte levels are required, as renal function may deteriorate.
• Monitor for signs of encephalopathy or worsening liver failure, and seek advice from a liver transplant unit if needed.

Criteria for Transfer to Liver Unit

• INR ≥ 3.0 or progressive increase in INR.
• Presence of hepatic encephalopathy (confusion, drowsiness, or coma).
• Hypotension that does not respond to fluid resuscitation.
• Metabolic acidosis (pH <7.3).
• Prothrombin time in seconds greater than time since overdose in hours (e.g., PT >36 seconds after 36 hours).

Poor Prognosis Indicators

• Arterial pH ≤ 7.3.
• Serum creatinine ≥ 300 μmol/L, indicating renal impairment.
• Prothrombin time ≥ 100 seconds.
• Grade III/IV hepatic encephalopathy (confusion, stupor, coma).

Special Considerations

• Pregnancy: NAC is safe for use in pregnancy and should be administered promptly to prevent liver damage in both mother and fetus.
• Chronic Ingestion: For patients who chronically ingest small overdoses (e.g., over days), management is more complex. NAC is often indicated if liver function is impaired or if symptoms of hepatotoxicity are present.

References

• Paracetamol Poisoning - BNF
• Management of Paracetamol Overdose - NCBI