Acetaminophen Overdose/Toxicity

Background

Acetaminophen is the most common OTC analgesic and one of the most common toxic exposures. Usually from intentional overdose (50%). Often accidently ingested as part of other medications, especially mixed opioid-acetaminophen combinations like Tylenol #1-3s.

Property Characteristic
Maximum therapeutic dose 4 grams daily in healthy adults; 2 grams daily in those with chronic liver disease
Toxic dose ingestion 10 grams or 200 mg/kg as a single ingestion or in one day; 6 g or 150 mg/kg for at least two days
"massive ingestion" >32 grams or > 500 mg/kg
Absorption completely absorbed in 4 hours, delayed by multiple ingestions or anticholinergics, opioids, etc.
Pharmacokinetics 100% bioavailable, 20% bound to serum proteins, elimination half-life is 2.5 hours
Metabolism Glucoronidation (50%), sulfation (30%), CYP (10%) which produces NAPQI which is the toxic metabolite (which is reduced with glutathione to form a renally excreted inactive metabolite)
Toxicity MOA Increased NAPQI generation depletes intracellular glutathione and then NAPQI overload leads to binding to hepatic macromolecules, causing centrilobular necrosis

Clinical Manifestations

Progression to Acute Liver Failure occurs in less than 1% of presentations in the Wester world.

Excess NAPQI binds to hepatic macromolecules, causing hepatocellular necrosis and potentially SIRS, MODS, ARDS, death. Initial clinical findings are nonspecific and delayed. There are four classic stages of acetaminophen toxicity:

  1. Stage 1 (<24 hours)
    • Mostly asymptomatic, can present with N/V, malaise, anorexia.
    • If the patient develops hypokalemia and metabolic acidosis this corresponds to an initial high APAP level.
    • In very severe ingestions (>75-100 g) the patient can become comatose or have a severe lactic acidosis secondary to metabolic decoupling of the electron transport chain.
  2. Stage 2 (2-3 days)
    • In this stage, clinical signs of hepatotoxicity develop:
      • Hepatocellular damage and hepatitis (RUQ pain, elevated aminotransferases)
      • Synthetic dysfunction (hypoglycemia, metabolic acidosis, elevated INR)
  3. Stage 3 (3-4 days)
    • Marked by a progression to fulminant hepatic failure:
      • severe lactic acidosis
      • coagulopathy
      • renal failure
      • encephalopathy
      • gastrointestinal symptoms
  4. Stage 4 (2 weeks)
    1. Either progresses to death, or slow recovery phase which takes 1-3 months in survivors. If no transplantation is required then recovery of hepatic function is usually near-complete.

Investigations

Treatment

  1. GI decontamination

    • Consider early activated charcoal (1 g/kg) through PO or NG routes if possible within 1-2 hours. If extended-release formulation acetaminophen or massive ingestion, can give this past 2 hours. Consider even up to 4 hours. Do not give if sedated unless ETT in situ.

    • Consider gastric lavage if presenting within 1 hour of massive ingestion

  2. N-acetylcysteine [NAC] (the antidote)

    • NAC is nearly 100% effective in prevention of hepatotoxicity if given within 8 hours of acute ingestion

    • Mechanism

      • (1) acutely, prevents NAPQI toxicity via glutathione repletion or via direct reduction back to acetaminophen

      • (2) afterwards, decreases hepatic necrosis via antioxidant effects, antineutrophil effect, increased tissue oxygen delivery

    • Route

      • IV administration is preferred over PO route esp in Canada.

    • Indication is depending on the nomogram and timeframe:

      • No further acetaminophen serum measurements are necessary once the need for acetylcysteine therapy has been determined until the completion of the course of therapy.

      • Massive ingestion (>150 mg/kg or >7.5 grams total) with results > 8 hours

      • <4 hours

        • If result within 8 hours, then wait on that and treat as indicated

        • If result not within 8 hours, give first dose and wait on results.

      • 4-24 hours

        • Same as above. Empirically give NAC if cannot get results before 8 hours. Modify approach after results back.

      • >24 hours or unknown

        • Draw labs ?levels and ?liver failure

        • Start NAC empirically ASAP

        • If acetaminophen is detectable, or ANY aminotransferases elevated, then treat with NAC.

        • Don't need to continue NAC if these are all normal.

  3. Risks

    • Anaphylactoid reaction. Risk factors are lower acetaminophen level, asthmatics. Treat with diphenhydramine, epinephrine, steroids, or stopping NAC. They will usually tolerate PO NAC if IV has too many problems.

    • Nausea/vomiting in 15%.

  4. Regimen

    • Standard protocol is 20-hour protocol:

      • Loading dose of 150 mg/kg over 15 minutes to 1 hour, then

      • First maintenance dose of 50 mg/kg over 4 hours, then

      • Second maintenance dose of 100 mg/kg over 16 hours

  5. When to stop?

    • Acetaminophen level is nondetectable (<66 umol/L), and

    • AST and ALT are < 100, or decreasing and <50% of peak, and

    • INR < 2.0, and

    • Patient is well, and

    • Minimum of 12 hours of NAC including the loading dose has been given.

  6. Hemodialysis

    • Because NAC is so effective, if it is available then HD is generally not needed at all.

    • There are no established criteria for this, and it is not routinely used. Discuss closely with toxicology/nephrology.

    • Consider in these situations:

      • Severe overdose (acetaminophen level >5.3 mm with coma and lactic metabolic acidosis)

    • Requires a higher rate (2x) of NAC infusion

  7. Liver transplantation

    • Qualification based on the King's College criteria for acetaminophen-induced liver injury

      • Arterial blood pH <7.3, or arterial lactate >3.0 mmol/L after adequate fluid resuscitation; OR

      • All of the following within a 24-hour period: grade 3 or 4 encephalopathy, INR >6.5, serum creatinine >3.4 mg/dL (301 micromol/L).

Outcomes

References