Paracetamol (PCM/Acetaminophen) Poisoning

Definition

Etiology and risk factors

Types of poisoning

1. Acute single ingestion
   • Deliberate self-harm or accidental ingestion of a large dose at one time.
2. Repeated supratherapeutic ingestion
   • Taking excessive doses over more than 24 hours.
   • Common when patients take several “cold/flu,” analgesic, or opioid-combination products containing paracetamol.

Factors increasing risk of hepatotoxicity

• Fasting, starvation, malnutrition
• Chronic alcohol use
• Enzyme-inducing drugs, for example phenobarbital and isoniazid
• Multiple paracetamol-containing preparations
• Prolonged high-dose use
• Delayed presentation

Pathogenesis

Paracetamol → CYP2E1 → NAPQI
NAPQI + glutathione → harmless mercapturic acid → urinary excretion

• Glucuronidation and sulfation become saturated.
• More NAPQI is formed.
• Hepatic glutathione stores become depleted.
• NAPQI binds covalently to hepatocyte proteins.
• This produces centrilobular (zone 3) hepatic necrosis, acute liver failure, metabolic acidosis, renal failure, and sometimes myocardial injury.

Clinical Features

Important Harrison points

• Early symptoms, usually within 4-12 hours, include nausea, vomiting, diarrhea, abdominal pain, and occasionally shock.
• Hepatic injury becomes apparent after 24-48 hours.
• Severe hepatic failure is usually maximal at 3-5 days.
• AST/ALT may exceed 10,000 IU/L.
• Acute renal injury and myocardial injury can occur.
• A typical biochemical clue is very high aminotransferases with relatively low bilirubin in a hyperacute liver injury pattern.
  Harrison’s Principles of Internal Medicine, 22e, p. 2711.

Investigations

Initial assessment

• Exact product and strength
• Amount ingested
• Time of ingestion
• Single versus repeated ingestion
• Co-ingestants, especially opioids and alcohol
• Intentional self-harm
• Previous liver disease, fasting, alcohol use, and medicines

Laboratory tests

1. Serum paracetamol concentration
   • Take at least 4 hours after a single acute ingestion.
   • A level before 4 hours is not useful for risk prediction.
2. Liver tests
   • AST, ALT, bilirubin, alkaline phosphatase
3. Liver synthetic function
   • PT/INR
4. Severity and complication tests
   • Blood glucose
   • Urea, creatinine, electrolytes
   • Arterial blood gas and lactate
   • CBC
   • Pregnancy test where appropriate
   • ECG and co-ingestant screen if indicated

Rumack-Matthew Nomogram

• A single acute ingestion
• The time of ingestion is known
• Serum level measured at least 4 hours after ingestion
• Ingestion occurred within the preceding 24 hours

Treatment line

• 150 micrograms/mL at 4 hours, or
• the corresponding declining line up to 24 hours.

Do not use the nomogram in:

• Unknown time of ingestion
• Repeated supratherapeutic ingestion
• Staggered overdose
• Presentation after 24 hours
• Modified-release ingestion, unless guided by a toxicology protocol

Management and Treatment

1. Immediate stabilization: ABCDE

• Airway: Protect airway if depressed consciousness or encephalopathy.
• Breathing: Oxygen and ventilatory support as required.
• Circulation: IV access, monitor vitals, treat shock with IV fluids and vasopressors if needed.
• Disability: Check mental status and blood glucose. Treat hypoglycemia promptly.
• Exposure: Look for co-ingestants and complications.

2. Gastrointestinal decontamination

Activated charcoal

• Give activated charcoal 1 g/kg orally, maximum usually 50 g, if the patient presents early and has a protected airway.
• Most useful within 4 hours of ingestion.
• Consider later administration in massive ingestion or modified-release preparations, with toxicology advice.

3. Specific antidote: N-acetylcysteine (NAC)

Indications for NAC

1. Serum paracetamol concentration plots at or above the treatment line.
2. Ingestion occurred more than 8 hours ago and a potentially toxic ingestion is suspected. Do not wait for the level.
3. Time of ingestion is unknown and paracetamol is detectable.
4. Repeated supratherapeutic ingestion with:
   • detectable paracetamol concentration, or
   • elevated AST/ALT.
5. Any evidence of hepatic injury with a history suggestive of paracetamol ingestion.
6. Acute liver failure where paracetamol toxicity is suspected, even if presentation is late.

Timing

• NAC is most effective when started within 8 hours of ingestion.
• Harrison’s states that it is effective early, but may retain partial benefit even when begun 24-36 hours after overdose.
• Therefore, never withhold NAC solely because the patient presents late.
  Harrison’s Principles of Internal Medicine, 22e, p. 2712.

4. NAC dosage regimens

A. Standard IV regimen: 21-hour, 3-bag protocol

• Persistent vomiting
• Encephalopathy
• Acute liver failure
• Poor oral absorption
• Inability to take oral medicine

B. Oral NAC regimen

• Loading dose: 140 mg/kg orally
• Then 70 mg/kg orally every 4 hours for 17 additional doses
• Total duration: 72 hours

Adverse effects of NAC

• Nausea and vomiting, especially oral NAC
• IV NAC may cause an anaphylactoid reaction: flushing, urticaria, bronchospasm, hypotension

• Temporarily stop or slow infusion.
• Give antihistamine.
• Treat bronchospasm/hypotension appropriately.
• Restart cautiously once symptoms resolve, as NAC remains essential.

5. Monitoring during treatment

• AST/ALT
• INR/PT
• Bilirubin
• Creatinine and urine output
• Glucose
• pH and lactate in severe poisoning
• Mental status for encephalopathy
• Serum paracetamol concentration

When to stop NAC

• Paracetamol remains detectable
• AST/ALT are rising
• INR is elevated
• Acidosis, renal impairment, or encephalopathy persists

• Paracetamol concentration <10 micrograms/mL
• AST/ALT normal or clearly falling
• INR <2.0
• Clinical and prognostic markers such as creatinine, lactate, pH and phosphate are improving, as outlined in the ACMT practice statement.

6. Management of acute liver failure

• Encephalopathy
• Coagulopathy
• Hypoglycemia
• Acidosis or elevated lactate
• Acute kidney injury
• Shock or multiorgan failure

Supportive treatment

• Continue NAC.
• Correct hypoglycemia with IV dextrose.
• Treat hypotension with fluids and vasopressors.
• Correct severe metabolic acidosis.
• Treat acute kidney injury and consider renal replacement therapy where indicated.
• Manage cerebral edema/raised intracranial pressure in fulminant hepatic failure.
• Early referral to a liver-transplant center.

Liver transplantation

• Worsening encephalopathy
• Progressive coagulopathy
• Severe lactic acidosis
• Renal failure
• Rising lactate

Short Practical Answer for Examination Writing

1. 0-24 h: nausea, vomiting, abdominal pain, malaise.
2. 24-72 h: RUQ pain, rising AST/ALT and INR.
3. 72-96 h: jaundice, severe hepatitis, encephalopathy, coagulopathy, hypoglycemia, metabolic acidosis, acute kidney injury, shock.
4. 4 days-2 weeks: recovery or death.

1. ABC stabilization and supportive care.
2. Activated charcoal 1 g/kg within 4 hours if indicated.
3. Start NAC immediately if the nomogram level is at/above treatment line, ingestion is >8 h old with suspected toxic dose, timing is unknown with detectable level, repeated overdose with raised transaminases, or established liver injury.
4. IV NAC: 150 mg/kg over 1 h, 50 mg/kg over 4 h, then 100 mg/kg over 16 h.
5. Continue NAC beyond 21 h if paracetamol remains detectable or liver function is worsening.
6. ICU care and early liver-transplant referral for acute liver failure.