Makindo Medical Notes

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💊 Paracetamol Overdose: Clinical Management Guide

📋 Overview

• Most common cause of acute liver failure in the UK & Europe.
• Accounts for up to 50% of all poisonings presenting to ED.
• Lethal dose usually 12–15 g, but toxicity possible at lower doses with risk factors.
• Clinical outcomes depend more on **timing** of NAC than on the absolute dose ingested.

🧬 Pathophysiology

• Normal metabolism: ~90% undergoes safe glucuronidation/sulphation, ~5–10% → CYP2E1 → NAPQI.
• Glutathione neutralises NAPQI. Liver stores ~30 mg/kg glutathione — rapidly depleted in overdose.
• NAPQI binds hepatocellular proteins → mitochondrial dysfunction, oxidative stress, necrosis.
• In severe cases: systemic inflammatory response, renal tubular necrosis, multi-organ failure.

Risk Factors Mechanisms:

• 🍺 Chronic alcohol → induces CYP2E1, ↓ glutathione → ↑ NAPQI.
• 🍽️ Malnutrition/fasting → low glutathione reserves.
• 🏥 Chronic liver disease → impaired detoxification capacity.
• 💊 Enzyme inducers (rifampicin, carbamazepine, phenytoin) → accelerate toxic metabolism.

Mnemonic MAL: Malnutrition, Alcohol, Liver disease → high risk of severe toxicity.

📈 Clinical Course

🔬 Investigations

• 💊 Plasma paracetamol level: only valid ≥4h post ingestion; plot on Rumack-Matthew nomogram.
• 🧪 LFTs: ALT/AST often peak 72–96h, may exceed 10,000 IU/L in severe toxicity.
• 🩸 INR/PT: best marker of synthetic failure; prolonged INR = poor prognosis.
• 🫁 ABG/VBG: metabolic acidosis → indicates mitochondrial dysfunction, poor outcome.
• 🫘 Renal function: creatinine rise suggests concurrent acute kidney injury.
• 🧠 Glucose monitoring: hypoglycaemia due to impaired gluconeogenesis.

Interpretation tip: Normal LFTs early on do not exclude significant toxicity.

💉 Management Principles

• Airway, breathing, circulation → stabilise first.
• Identify time & dose of ingestion; always consider staggered ingestions.
• Charcoal and NAC are complementary: charcoal reduces absorption, NAC repairs metabolism.

Activated Charcoal

• Indicated if within 1h of ingestion ≥150 mg/kg.
• 50 g orally/NG tube if patient alert or airway protected.
• Not given if vomiting, drowsy, or aspiration risk.

NAC Indications (UK)

• Plasma paracetamol above single treatment line (100 mg/L at 4h).
• ≥150 mg/kg ingestion where level not yet available.
• Presentation >24h with detectable paracetamol OR any liver injury (↑ALT, INR>1.3, jaundice).

NAC Mechanism

• Replenishes glutathione → detoxifies NAPQI.
• Improves hepatic microcirculation, acts as antioxidant.
• Remains effective even if given late, though best within 8h.

NAC Regimen (3-bag, IV)

• Bag 1: 150 mg/kg in 200 mL over 1h
• Bag 2: 50 mg/kg in 500 mL over 4h
• Bag 3: 100 mg/kg in 1L over 16h

💡 Use ceiling weight of 110 kg for obese patients.

NAC Adverse Effects

• Rash/flushing (common, mild) → continue.
• Anaphylactoid reaction (bronchospasm, hypotension) → stop temporarily, give antihistamine, restart slowly.

📊 Prognosis

Poor prognostic indicators (Mnemonic: PHAIL):

• PH <7.3 (arterial)
• High INR ≥100s
• Azotaemia (Creatinine ≥300 µmol/L)
• INR rising despite NAC
• Liver encephalopathy (Grade III/IV)

➡️ Criteria for urgent liver transplant referral: INR ≥3, encephalopathy, metabolic acidosis, renal failure.

⚠️ Complications

• Fulminant hepatic failure (risk of cerebral oedema, sepsis, multiorgan failure)
• Acute kidney injury (tubular necrosis, often delayed)
• Lactic acidosis (poor prognostic marker)

👶 Special Cases

• Pregnancy: NAC safe; protects both mother & fetus. Delay worsens outcomes for both.
• Staggered ingestion: Nomogram not applicable; treat if dose ≥75 mg/kg in 24h OR any liver injury.
• Chronic ingestion: Consider NAC if symptomatic or abnormal LFT/INR.
• Co-ingestions: Salicylates, opioids, benzodiazepines → alter presentation and management.

📋 Quick Revision Checklist

1. ⏰ Establish time & dose ingested.
2. 💉 Take paracetamol level (≥4h).
3. 🧪 Check LFTs, INR, glucose, VBG.
4. 🖤 Charcoal if <1h and airway safe.
5. 💊 Start NAC if indicated.
6. 📞 Refer to liver unit if PHAIL features present.

🧑‍⚕️ Case 1: Early Presentation (Safe Window)

A 20-year-old student presents 3 hours after taking 20 × 500 mg paracetamol tablets following an argument with her partner. She has mild nausea but is alert and stable. Past medical history unremarkable.

• Total dose: 10 g (~160 mg/kg for 62 kg patient)
• Action: Too early for paracetamol level (needs ≥4h). Admit, monitor, repeat bloods at 4h.
• If 4h level above 100 mg/L line → start NAC.
• Learning point: Always wait until 4h for reliable levels, unless ingestion is staggered/uncertain.

🧑‍⚕️ Case 2: Delayed Presentation (High Risk)

A 35-year-old man arrives 14 hours after ingesting 25 g paracetamol (50 tablets). He reports ongoing vomiting and confusion. Examination: jaundiced sclera, RUQ tenderness.

• Total dose: 25 g (~300 mg/kg for 80 kg male)
• Investigations: Paracetamol level detectable; ALT 5,000; INR 2.4
• Management: Immediate NAC (do not wait for nomogram). Admit to HDU. Discuss with liver unit if INR rises to ≥3 or encephalopathy worsens.
• Learning point: Beyond 8h → always start NAC if significant ingestion; nomogram less useful late.

🧑‍⚕️ Case 3: Staggered Overdose

A 45-year-old woman with chronic back pain admits to taking “8–10 tablets every few hours” over the past 2 days (estimated 30 g total). She feels nauseated but not confused. Past history: fatty liver disease.

• Problem: No single ingestion time → nomogram not applicable.
• Action: Start NAC empirically, especially with risk factors (liver disease).
• Learning point: Staggered ingestions = treat if total dose ≥75 mg/kg in 24h or LFTs abnormal.

🧑‍⚕️ Case 4: Special Group – Pregnancy

A 26-year-old woman, 28 weeks pregnant, presents 5 hours after ingestion of 15 g paracetamol. She is well but anxious for the baby.

• Total dose: 15 g (~200 mg/kg)
• Action: Paracetamol level ordered at 4h; start NAC immediately if above line.
• Key point: NAC is safe in pregnancy — protects both mother and fetus. Do not delay.

🧑‍⚕️ Case 5: Poor Prognosis Indicators

A 40-year-old man presents 4 days after a massive overdose. He is jaundiced, confused, hypotensive, and oliguric.

• Results: pH 7.25, Creatinine 350 µmol/L, INR 120, Grade III encephalopathy.
• Interpretation: Meets multiple “PHAIL” poor prognosis criteria.
• Action: Emergency referral to liver transplant unit; continue NAC until outcome decided.

📚 References

• BNF: Paracetamol Poisoning
• Management of Paracetamol Overdose (NCBI)
• TOXBASE (UK National Poisons Information Service)