Poisoning from - paracetamol
Description
- Commonest pharmaceutical overdose and the commonest cause of acute liver failure in Australia and the UK
- Asymptomatic in the first 24 h - the antidote must be given before any clinical sign appears
- Treatment decisions rest entirely on dose, timing and level - never on how the patient looks
Ingestion patterns - each has its own pathway
| Pattern | Definition |
|---|---|
| Acute | All ingested within an 8-hour window |
| Staggered | Multiple ingestions over >8 h with intent to self-harm |
| Repeated supratherapeutic (RSTI) | Excess taken over time for therapeutic purpose |
| Modified-release (Panadol Osteo) | Separate algorithm - delayed and prolonged absorption |
| IV paracetamol | Dosing errors, especially <50 kg and paediatrics |
Phases
- I (0-24 h) - asymptomatic or nausea/vomiting, malaise
- II (24-72 h) - RUQ pain, transaminases rise, INR rises
- III (72-96 h) - peak hepatotoxicity: jaundice, encephalopathy, coagulopathy, lactic acidosis, AKI, hypoglycaemia
- IV (4 d-2 wk) - recovery, complete if survived
Epidemiology
- ~10,000 Australian hospital presentations/yr for paracetamol poisoning
- Peak: adolescent and young adult females (impulsive self-poisoning)
- Deaths concentrated in unintentional RSTI and late presentations, not in the classic acute overdose
- Australia up-scheduled modified-release paracetamol to Pharmacist Only (S3) in 2020 after a rise in severe MR poisonings
- ~1-2% of acute overdoses develop hepatotoxicity when NAC is given within 8 h; risk rises steeply after 8-10 h
Aetiopathogenesis
- Therapeutic doses: ~90% glucuronidation + sulfation -> non-toxic conjugates
- ~5-10% via CYP450 -> NAPQI (N-acetyl-p-benzoquinone imine)
- Predominantly CYP2E1, lesser CYP3A4 and CYP1A2
- NAPQI is detoxified by conjugation with glutathione
- Overdose:
- Conjugation pathways saturate -> inc fraction through CYP
- Glutathione depleted (<30% of normal) -> free NAPQI
- -> covalent binding to hepatocyte proteins, mitochondrial dysfunction, oxidative stress
- -> centrilobular (zone 3) necrosis (highest CYP2E1 density, lowest O2 tension)
- NAC works by replenishing cysteine -> glutathione, and by direct NAPQI scavenging and improved microcirculatory O2 delivery
- Fully protective if glutathione is restored before it is exhausted -> hence the 8-hour window
Kinetics in overdose - why the 4-hour rule exists
- Large doses -> delayed gastric emptying / pylorospasm + tablet agglomeration + saturated absorption
- -> time to peak concentration is later than after therapeutic dosing
- -> a level before 4 h cannot be interpreted; and in massive or modified-release ingestion an early level near the line may still be rising - repeat it
Risk modifiers
- inc CYP2E1: chronic alcohol use, isoniazid, rifampicin, phenytoin, carbamazepine
- dec glutathione: malnutrition, anorexia, HIV, cystic fibrosis, chronic illness, acute starvation
- These matter most in RSTI, not in single acute overdose - the Australian nomogram has a single treatment line
Diagnosis
Risk assessment - the decision variables
- Dose ingested (mg/kg), time of ingestion, formulation, pattern
- Acute IR ingestion is potentially toxic at >=200 mg/kg or 10 g, whichever is less
Paracetamol level
- Take at >=4 h post-ingestion (or immediately if presenting later)
- Plot on the Australian/New Zealand nomogram: single treatment line of 150 mg/L (1000 micromol/L) at 4 h, declining with a half-life of 4 h
- No separate "high-risk" line in the ANZ guideline
- Repeat the level if massive ingestion or modified-release - an early value below the line may still be climbing
Other bloods
- ALT (the marker of injury), INR, UEC, VBG/lactate, BSL, FBE
- ALT rising above the reference range is hepatotoxicity - waiting for jaundice is too late
- Paracetamol level plus ALT is the pair that decides everything at the end of the infusion
Pattern-specific
| Pattern | Approach |
|---|---|
| Acute IR | Level at 4 h -> nomogram |
| Staggered / unknown time | Paracetamol level + ALT; treat if level >=20 mg/L (132 micromol/L) or ALT raised |
| RSTI | Level + ALT; treat if either abnormal |
| Modified release | Charcoal; level at 4 h AND again 4 h later - treat if EITHER is above the line; continue NAC until levels falling and ALT normal |
| Massive (>=30 g or >=500 mg/kg, or level >2x line) | Increased NAC dose |
Markers of established liver failure
- INR >2 at 24 h, or >3.5 at 48 h
- Lactate, acidosis, hypoglycaemia, creatinine rise, encephalopathy
King's College criteria for transplant referral
- Arterial pH <7.3 after adequate fluid resuscitation, OR all three of:
- INR >6.5 (PT >100 s)
- Creatinine >300 micromol/L
- Grade III-IV encephalopathy
- Lactate >3.5 mmol/L early or >3.0 after resuscitation is an additional adverse marker
Management
Time-critical. NAC within 8 h of an acute ingestion is essentially fully protective; efficacy falls steeply thereafter but NAC still benefits even at 24 h and in established failure.
1. Resuscitation and risk assessment
- ABC, BSL, antiemetic (ondansetron/metoclopramide)
- Call the Poisons Information Centre - 13 11 26 (Australia-wide)
- Consider co-ingestants - the paracetamol is often not the dangerous drug
2. Decontamination
- Activated charcoal 50 g if presenting within 2 h of a significant ingestion
- Extend to up to 4 h for massive or modified-release ingestion
- Only if airway protected and cooperative; do not force
3. Acetylcysteine - the two-bag regimen (Australian standard)
- 200 mg/kg IV over 4 h, then 100 mg/kg over 16 h
- Replaced the three-bag regimen: same efficacy, markedly fewer adverse reactions
- Massive overdose - level >2x the nomogram line, or >=30 g / >=500 mg/kg ingested: double the second bag to 200 mg/kg over 16 h
- Even higher concentrations (>=3x line) may need further dose increases - discuss with toxicology
Who gets NAC
- Level above the nomogram line, OR
- Presentation >8 h after a potentially toxic ingestion - start NAC immediately, do not wait for the level, OR
- Unknown time of ingestion, staggered ingestion with raised level or ALT, OR
- Any patient with raised ALT attributable to paracetamol
4. Anaphylactoid reactions to NAC
- ~10-20% - flushing, urticaria, bronchospasm, hypotension
- Non-IgE (direct histamine release); rate-related and commonest during the first bag
- Management: pause or slow the infusion, antihistamine +/- salbutamol, then restart at a lower rate
- *Do not abandon NAC - it is not a true allergy and the patient still needs the antidote*
- NAC prolongs INR mildly by direct effect on clotting factor assays (an INR of ~1.3-1.5 on NAC is not liver failure)
5. Ending the infusion
- At the end of the 20 h: recheck paracetamol level, ALT, INR
- Cease if: paracetamol <10 mg/L (66 micromol/L) AND ALT normal or falling AND INR <2
- Continue at 100 mg/kg/16 h if: paracetamol still detectable, ALT rising, or INR rising
- Continue until ALT has clearly peaked and is falling and INR is improving - not to a fixed duration
6. Established hepatotoxicity / acute liver failure
- Continue NAC until recovery
- N-acetylcysteine, glucose infusion for hypoglycaemia, correct electrolytes
- Do not correct INR with vitamin K or FFP unless bleeding - it is the key prognostic marker
- Early discussion with a liver transplant unit - do not wait until criteria are met
- Manage cerebral oedema, renal replacement therapy for AKI
7. Every patient
- Psychiatric and risk assessment before discharge - the overdose, not the paracetamol, is the presenting problem
- Counsel on safe paracetamol dosing; maximum 4 g/day in adults, less with low body weight, malnutrition or liver disease
- Means restriction, follow-up, GP communication
Associations
- Deliberate self-harm, depression, alcohol and substance use disorder
- Chronic alcohol use - inc CYP2E1 + dec glutathione
- Malnutrition, anorexia nervosa, HIV, cystic fibrosis
- Enzyme-inducing drugs - isoniazid, rifampicin, phenytoin, carbamazepine, St John's wort
- Chronic pain and opioid-paracetamol combination products (a common route to unintentional RSTI)
- Low body weight and paediatric IV dosing errors
- Gilbert syndrome: reduced glucuronidation, theoretical risk - not a treatment modifier
Natural history & complications
- Treated within 8 h of an acute ingestion: hepatotoxicity is rare and death is very rare
- Untreated significant ingestion: hepatotoxicity in ~50%, ALF in a minority
- If the patient survives, hepatic recovery is complete - paracetamol does not cause chronic liver disease
- Mortality overall <0.5%; ~10-20% among those who reach acute liver failure without transplant
- Poor prognosis: acidosis, lactate, INR trajectory, creatinine, encephalopathy grade (King's College criteria)
- Complications: acute liver failure, cerebral oedema, AKI (may occur without hepatotoxicity - direct tubular NAPQI toxicity), pancreatitis, lactic acidosis, hypoglycaemia, death
- Late presenters and repeated supratherapeutic ingestion account for a disproportionate share of deaths
🔒
6 more sections, plus exam facts
Premium unlocks every note across every specialty, and the full exam fact library behind it.
Get premium access