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    Acetaminophen Overdoses

    Toxicology

    Last Updated Oct 31, 2018
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    Context

    • Acetaminophen is a commonly available analgesic and antipyretic medication. 5-15% of acetaminophen is metabolized to N-acetyl-P-benzoquinoneimine (NAPQI) which causes hepatocellular death and is the leading cause of acute liver injury in North America.

    Typical Course

    • May be asymptomatic or have nonspecific GI symptoms.
    • Transaminases can begin to rise within 24 hours.
    • In severe poisoning, liver injury progresses to coagulation defects, jaundice, encephalopathy, hypoglycemia, lactic acidosis, and hepatorenal syndrome within 3-5 days.
    • Death occurs from hepatic failure, cerebral edema or multiorgan failure. In patients who survive, liver heals without evidence of injury.
    • In rare cases of acute massive overdose, patient may develop early lactic acidosis and coma independent of liver toxicity.
    • After chronic or repeated supra-therapeutic ingestion, patient may present with elevated transaminases and evidence of impaired liver function.
    • Most deaths occur in patients presenting late or after excessive doses for several days.
    • Do not rely on history of dose or substance ingested; draw serum acetaminophen level in all patients with history of overdose.

    Toxic Dose

    Acute, single ingestion:

    • Adult or Child (6-years or older): ≥ 5 g or 200 mg/kg (whichever is less) may cause hepatotoxicity.
    • Child (younger than 6-years-old): ≥ 200 mg/kg may be associated with hepatic injury.

     

    Chronic, repeated supra-therapeutic ingestion can result in toxicity:

    • Adult or Child (6-years or older):
      • ≥ 10g or 200 mg/kg (whichever is less) over a single 24-hour period.
      • ≥ 6g or 150 mg/kg (whichever is less) per 24 hours for 48 hours or longer.
    • Child (younger than 6-years-old):
      • > 200mg/kg over a single 24-hour period.
      • > 150 mg/kg/day for 48 hours.
      • > 100 mg/kg/day for 72 hours or longer.
    • Patients at increased risk (chronic alcohol use, isoniazid therapy, malnourished):
      • > 4 g/day or 100 mg/kg/day (whichever is less).

    Clinical Pitfalls

    • Failure to consider acetaminophen poisoning in known or suspected overdoses.
    • Failure to consider acetaminophen as cause for acute liver injury even if acetaminophen level is non-detectable.
    • Failure to recognize massive acetaminophen ingestion as cause for altered mentation and lactic acidosis BEFORE transaminases become abnormal.
    • Failure to start NAC in patients with known or suspected acetaminophen overdose who present close to or over 8 hours post ingestion. In these cases start NAC BEFORE you have lab results back.
    • Starting NAC less than 4 hours from ingestion – unless massive ingestion presenting with coma and acidosis.
    • Misapplication of acetaminophen nomogram:
      • plotting level on nomogram when time of ingestion is unknown;
      • relying on levels obtained < 4 hours or > 24 hours after ingestion;
      • failure to recognize that your lab may not be able to detect low levels of acetaminophen that would be considered above the nomogram line if obtained 20-24 hours after ingestion;
      • not repeating acetaminophen level in 4 hours if ingestion includes a sustained release acetaminophen product or there was co-ingestion of anticholinergics or opioids.
    • Failure to consider hemodialysis in massive acetaminophen ingestion who present with coma and lactic acidosis.
    • Failure to consult your poison centre

    Recommended Treatment

    • N-acetylcysteine (NAC) is most effective if initiated within 8-10 hours following acute overdose, but is still effective if begun later when liver injury is evident and acetaminophen levels may be non-detectable.
    • Measure serum acetaminophen level and liver enzymes to determine risk of toxicity and need for administration of NAC in the following patients:
      • Acute overdose of > 7.5 g or ≥ 200 mg/kg acetaminophen (whichever is less), or unknown amount, OR
      • Intentional overdose of any substance, OR
      • Repeated supra-therapeutic ingestion of acetaminophen (chronic excessive), OR
      • Patients presenting with unexplained metabolic acidosis.
    • Activated charcoal should be administered within 1-2 hours of acute
      • May be considered more than 2 hours post ingestion for patients who have ingested:
        • a large overdose,
        • an extended-release preparation, or
        • co-ingested opioids or anticholinergic agents (eg. diphenhydramine, antihistamines).
    • Activated charcoal is generally not indicated for patients with repeated supra-therapeutic ingestions or those who cannot protect their airway.

    Risk Assessment

    Acute overdose within previous 24 hours:

    • Measure initial acetaminophen level at 4 hours post ingestion or upon presentation if later than 4 hours post ingestion and plot on nomogram (http://www.ars-informatica.ca/toxicity_nomogram.php?calc=acetamin).
    • Beyond the 20 hour mark on the nomogram toxic acetaminophen levels may be below the level of your labs detection. Some labs report negative acetaminophen level as < 66 mmol/L. There could still be acetaminophen present in toxic amounts but below this limit of detection. In these cases NAC should be started and continued until clinical trajectory is known.
    • Levels drawn less than 4 hours post ingestion should be repeated at 4 hours after ingestion.
    • If exact time of ingestion is unknown, plot on nomogram using “worst possible scenario” or earliest possible time of ingestion.
    • For patients who ingest extended-release products or co-ingested opioids or anticholinergic agents, repeat level after an additional 4 hours, if first level is nontoxic (“below the line”).
    • Obtain baseline AST.

     

    Acute overdose presenting more than 24 hours or ingestion time unknown:

    • Measure initial serum acetaminophen level (cannot plot on nomogram).
    • Obtain liver enzymes, INR, bilirubin, creatinine, urea, glucose, and electrolytes.

     

    Repeated supra-therapeutic ingestions (chronic excessive):

    • Measure initial serum acetaminophen level (cannot plot on nomogram).
    • Obtain liver enzymes, INR, bilirubin, creatinine, urea, glucose, and electrolytes.

     

    NAC indicated when:

    • Serum acetaminophen level is greater than the treatment line on nomogram in acute poisoning, OR
    • Patient has signs or symptoms of hepatic injury regardless of acetaminophen level or time of ingestion, OR
    • Liver enzymes or serum acetaminophen levels are unavailable or will be delayed, OR
    • Patient presents with early metabolic acidosis and coma following a massive overdose, even prior to obtaining acetaminophen level, OR
    • Following repeated supra-therapeutic ingestion (chronic excessive), in patients with either an AST or ALT > 50 IU/L and/or acetaminophen level > 66 μmol/L.
    • Symptomatic and supportive care should be provided as indicated and may include antiemetics, glucose for hypoglycemia, potassium for hypokalemia, vitamin K and fresh frozen plasma for coagulopathy or bleeding.
    • Hemodialysis removes acetaminophen and should be considered early in patients following massive ingestion with coma and/or lactic acidosis.
    • 4-methypyrazole (Fomepizole) ( used to treat toxic alcohols) may be useful in patients with massive acetaminophen ingestion.

    Criteria For Hospital Admission

    Any patient requiring NAC therapy or psychiatric evaluation for self-harm.

    Criteria For Transfer To Another Facility

    Transfer when any of the following is not available locally:

    • Patient requires ICU care, or
    • NAC is required,
    • Necessary consultation, or
    • Necessary laboratory tests.

    Consult

    BC Drug and Poison Information Centre at 604-682-5050 or 1-800-567-8911.

    Criteria For Safe Discharge Home

    • Acetaminophen levels are non-treatable and no evidence of liver injury, or
    • Completion of NAC therapy and resolution of hepatic injury (if any occurred) and
    • Acute psychiatric conditions are stabilized.

    Quality Of Evidence?

    Justification

    • Moderate for NAC as therapy for acetaminophen poisoning.
    Moderate
    • Low for determining the threshold to start NAC, how to best dose NAC, as well as transplantation, decontamination, and other adjunct therapies.
    Low

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