• 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.

• 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.

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).

• 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

• 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.

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.

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

Transfer when any of the following is not available locally:

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

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

• 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.

1. Interactive Rumack-Matthew Nomogram for Acetaminophen Toxicity

   
   

1. Poison Management Manual (PMM), BC Drug and Poison Information Centre, 2015

   
   

2. Brok J, Buckley N, Gluud C. Interventions for paracetamol (acetaminophen) overdose. Brok J, editor. Cochrane Database Syst Rev. Chichester, UK: John Wiley & Sons, Ltd; 2006 Apr 19;80(2):CD003328.