FRCA Notes

Paracetamol Overdose

Paracetamol overdose hasn't appeared as a CRQ yet, though is certainly fair game for both Primary and Final written and oral exams.

The topic often becomes laboriously bogged down in talk of overdose timings, nomogram applicability and other such detail.

While important, the specifics of these can often be found in local trust paracetamol overdose pathways, TOXBASE or the resources below.

Thus in a rare break from attempted consummate notes, this section provides a more 'skeletal' approach to the topic.

Resources

  • Paracetamol overdose causes 150 - 200 deaths/yr through liver failure and is a common indication for liver transplant
  • Hepatotoxicity occurs at doses >150mg/kg
  • Some patients may be at higher risk of liver injury, and the toxic dose is deemed 75mg/kg in:
  1. Those with depleted hepatic glutathione stores:
    • Malnutrition including anorexia/bulimia and cystic fibrosis
    • HIV
    • Alcoholism
    • Chronic liver disease
    • Chronic kidney disease

  2. Those taking CYP450 enzyme-inducing drugs
    • Phenytoin
    • Carbamazepine
    • Rifampicin
    • Phenobarbitone

Hepatic metabolism

  • Normal metabolism is hepatic (CYP2E1) via:
    • Conjugation (90%) to predominantly glucuronide conjugates, but also cysteine and sulphate conjugates too
    • Oxidation (10%) to N-acetyl-p-amino-benzoquinone imine (NAPQI)
      • A small amount of this highly toxic compound is produced with therapeutic dosing
      • It normally undergoes glutathione conjugation to a harmless metabolite
  • Approximately 2% is excreted unchanged in the urine

Toxicity

  • In overdose, the normal hepatic conjugation pathways become saturated
  • There is increased NAPQI production, and hepatic glutathione stores are rapidly exhausted
  • NAPQI then forms covalent bonds with cysteine (sulfhydryl) groups on hepatocytes
    • This causes centrilobular hepatic necrosis and cell death
    • Injury begins once glutathione stores are 70 - 80% depleted

  • There is generally retained consciousness and patients may be asymptomatic, particularly in the first 24hrs
  • Often the only symptoms within 24hrs are nausea/vomiting, abdominal pain and rarely coma (if plasma concentration >800mg/L)

Common features

  • Nausea and vomiting
  • (Epigastric) abdominal pain
  • Sweating

  • Patients may also suffer:
    • Cholestasis
    • Erythema/urticaria and mucosal lesions
    • Delayed hypoglycaemia

Biochemical features

Liver function tests Renal function Haematological Others
↑ ALT/AST ↑ creatinine ↑ INR/PT Hypoglycaemia
↑ ALP Anaemia ↑ Lactate
↑ Bilirubin Metabolic acidosis

Severe features

  • Vasodilatory shock
  • Cerebral oedema, encephalopathy and coma
  • Oliguria, loin pain, haematuria and proteinuria indicate incipient renal failure
  • Hepatic failure (from 48hrs)
  • Acute haemolytic anaemia

  • Initial management focuses on:
    • History of time of/since ingestion and whether ingestion was staggered or not
    • Investigations including U&E, LFT, INR, bicarbonate and paracetamol levels

Activated charcoal

  • Is indicated if <1hr since ingestion and >150mg/kg dose

N-acetyl cysteine

  • Treatment involves replenishing hepatic glutathione, typically with NAC 300mg/kg (or oral methionine)
  • NAC is almost 100% effective if administered within 8hrs of ingestion

  • NAC is hydrolysed to cysteine, which itself is converted to glutathione
  • Methionine encourages conversion of cysteine to glutathione

  • NAC is associated with anaphylactoid reactions (30%)
    • Risk factors include 1st NAC exposure and fast infusion rate
    • They may have tachycardia, wheeze and urticaria although hypoxia and hypotension are typically absent
    • Management is by:
      • Stopping the infusion
      • Administration of chlorphenamine and salbutamol e.g. nebuliser
      • Restarting infusion at lower rate
    • Does not preclude future use of NAC

Regimens

  • The standard regimen is 300mg/kg over 21hrs
  • The modified SNAP protocol over 12hrs
    • Still provides 300mg/kg
    • Generates lower peak plasma concentration of NAC and therefore lower risk of anaphylactoid reactions

Early presentation (<24hrs) of non-staggered overdose

  • Paracetamol level at presentation or 4hrs post-ingestion (whichever is later) is taken
  • If >8hrs since ingestion and >150mg/kg, start empirical NAC until level back
  • Plot on nomogram to guide ongoing therapy

Late presentation (>24hrs) of non-staggered overdose

  • Patients are at higher risk, and should be treated with NAC
  • Paracetamol levels may be unreliable
  • The decision about starting/stopping NAC should be based on clinical and biochemical markers e.g. jaundice, INR >1.3, raised ALT, hepatic tenderness

Staggered overdose

  • Should receive NAC if they've ingested >150mg/kg in any 24hr period

  • Patients with paracetamol levels >700mg/L may require haemodialysis
  • If haemodialysed, the dose of NAC should be doubled

King's College Criteria

  • Predict patients with poor prognosis and recommends who should be referred for liver transplant (at least 3 of 4 within 24hrs needed):
    • pH <7.30
    • PT >100s (INR >6.5)
    • Grade 3 or 4 encephalopathy
    • Creatinine >300μmol/L

  • There are modified criteria (e.g. Cr>200μmol/L, INR >3) too