Paracetamol Overdose

• Overdose is 150 mg/kg (7.5, 9, 10.5 gram for 50, 60, 70 kg patient respectively)
  Phase I:
  
  • 12-24 hours
  • GI symptoms, N/V, anorexia, diaphoresis, pallor
  • coma is rare
  • most patients recover and does not go beyond Phase I
  Phase II
  
  • if toxicity continues, this is the latent phase of up to 48 hours
  • Symptoms abate and patient feels better BUT
    rising and striking levels of AST/ALT, PT/INR, bilirubin, lactate, phosphate
  • RUQ pain due to liver enlargement and tenderness
  • most patients does not go beyond this phase
  Phase III
  
  • rare, serious hepatic necrosis; 3-5 days after ingestion
    
  • + jaundice, confusion, stupor, coagulation defect, hypoglycemia, encephalopathy, renal failure, cardiomyopathy
  • death if it occurs is due to fulminant hepatic failure
  • mortality rate for toxic level without treatment is 3-4%
    
  
  
• Paracetamol metabolism: in the liver
  - 3 pathways for metabolism; (1) and (2) are major
  (1) Glucoronidation: glucoronide conjugate (not toxic) -> cleared by the kidneys
  (2) Sulfation: sulfate conjugate (not toxic) -> cleared by the kidneys
  (3) Cytochrome p450: NAPQI (N-Acetyl P-benzoQuinone Imine) (toxic) -> conjugates with sulfhydryl group of glutathione -> excreted to kidneys
  
  OD: glutathione is saturated with lots of NAPQI and is depleted
  NAPQI is toxic to liver = hepatoxicity and nephropathy
  
  
• N-acetylcysteine (Mucomyst, Parvolex): precursor of Glutathione
  Guidelines for Management of AOD (pdf)
  
  
• Acetaminophen level
  
  • take assay at 4 hours post-ingestion or ASAP if more than 4 hours
  • above 200 ug/mL at 4 hours or 50 ug/mL at 12 hours = hepatotoxic
  • Rumack-Matthew normogram: in order to err on the safe side, treatment line is drawn 25% below Rumack-Matthew line
  • if below treatment line, NAC is unnecessary, or if already started, may discontinue
  • if above treatment line, NAC complete course should be given even subsequent levels are below treatment line
    
    
  • If a patient presents within 4 hours, withhold NAC until levels are out, PROVIDED that initiation of treatment is not delayed beyond 8 hours post-ingestion
  • If a patient presents more than 8 hours, start NAC REGARDLESS of amount ingested. Do not wait for assay.
  
  
• Management: ABCDEFG
  (1) Activated Charcoal: 50 g if less than 4 hours ( >2 hours, data is limited)
  - 1g/kg, resuspended with water to achieve 25% concentration, dose is 10:1 ratio of activated charcoal to toxin
  - not absorbed: PHAILS
  
  • Pesticides, Potassium
  • Hydrocarbons
  • Acids, Alkalis, Alcohol
  • Iron, Insecticides
  • Lithium
  • Solvents
    
  
  (2) N-acetylcysteine:
  IV: total of 300 mg/kg in 24 hours
  
  • 150 mg/kg + 200 mL 5% Dextrose in 15-60 mins
  • 50 mg/kg + 500 mL 5% Dextrose in 4 hours
  • 100 mg/kg + 1L 5% Dextrose in 16 hours
    = anaphylactoid reaction: PFUN (Pruritus, Flushing, Urticaria, Nausea, etc)
    Tx: Give slower
  Oral: 140 mg/kg LD, then 17 doses of 70 mg/kg at 4-hour intervals
  - total duration: 72 hours
  
  
• LABS
  
  • healthy, asymptomatic patient presenting early, only acetaminophen level
  • in symptomatic or with elevated acetaminophen, ALT and AST, then daily
  • in patients with liver injury: bilirubin, PT/INR, creatinine, BUN, electrolytes, blood glucose, lactate, phosphate, pH tests
    
    
  • For Extended Release tablets: take it at 4 hours post-ingestion as there is no protocol, but some do a second level 4-6 hours after first assay
    - if either is above treatment line, start NAC
    - if either is below, discontinue NAC if already started
    

• Special considerations:
  
  • Children below 6yo, hepatotoxicity is rare due to different metabolism, same approach but different dose
    
  • Pregnant: treat as non pregnant although NAC enters placental barrier
  • >24 hours, ALT/AST should be taken; IV NAC improves survival for those on fulminant hepatic failure; Rumack-Matthew is useless
    
  • Alcoholics: more prone to hepatotoxicity, but same approach
    
  • Repeated supratherapeutic (chronic) OD: ingestion of toxic amounts over a period of longer than 8 hours
    - Rumack-Matthew is useless
    - NAC should be given if assay is >10 mg/L or with liver injury (AST/ALT)
    - NAC for 12 hours, then evaluate
    - may discontinue if clinically well, AST/ALT improving, assay <10>
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