Acetaminophen Toxicity

Aka: Acetaminophen Toxicity, Acetaminophen Overdose, Acetaminophen Poisoning, Tylenol Overdose, APAP Nomogram, Rumack-Matthew Acetaminophen Nomogram, APAP Overdose

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II. Epidemiology

  1. Over 136,000 Acetaminophen reported Poisonings per year in U.S.
    1. Half of Overdoses are in combination with other agents
  2. Accounts for 12% of all poison related deaths in U.S. (400-500 deaths per year)
  3. Most common cause of Acute Liver Failure in United States (42% of cases)
  4. Inaccurate Acetaminophen dosing in children is common
    1. Study of n=100, retrospective questionnaire
    2. Adults knowing the dosing interval: 86%
    3. Adults accurately dosing and measuring the med: 30%
      1. Only 40% stated the correct dose
      2. One third inaccurately measured the medication
    4. Reference
      1. Simon (1997) Arch Pediatr Adolesc Med 151:654-6 [PubMed]
  5. In 2024, a manufacturer has chosen to market a gummy, 80 mg version of Acetaminophen
    1. Creating a candy-like edible of among the most lethal medications in Overdose may be unwise
  6. Acetaminophen is often marketed OTC with confusing product names in combination with other agents
    1. Example: Motrin Dual Action contains both Ibuprofen and Acetaminophen
    2. When combination products are in turn combined with other medications, toxic levels are easily reached

III. Mechanism: Hepatoxicity

  1. Acetaminophen Pharmacokinetics
    1. Absorbed primarily from the Small Intestine
    2. Serum concentration peaks 60-90 minutes after ingestion (delayed in Overdose or long-acting form)
    3. Half-Life is 2-3 hours (at standard doses in a patient with normal Renal Function)
  2. Acetaminophen metabolism
    1. Benign metabolites are renally excreted after conjugation (only 5% is renally excreted unchanged)
    2. Primary metabolism pathway is conjugation (90% of Acetaminophen)
      1. Glucuronidation (66%)
      2. Sulfation (33%)
    3. Alternative metabolism by Cytochrome P450-2E1 to N-acetyl-p-benzoquinoneimine (NAPQI)
      1. Oxidative pathway that accounts for 5-15% of Acetaminophen metabolism
      2. Up-regulated pathway when Glucuronidation and sulfation are overwhelmed
        1. Glutathione is an natural antidote to NAPQI, but is depleted in Acetaminophen Toxicity
      3. NAPQI binds hepatic Proteins and is directly hepatotoxic
        1. NAPQI is normally conjugated with glutathione into benign Cysteine and Mercaptopurine
      4. Excessive NAPQI binds mitochondria
        1. Results in phosphorylation of c-Jun N-terminal Kinase (JNK)
        2. Phosphorylated JNK stimulate mitochondrial superoxides
        3. Superoxides react with nitric oxide to form peroxynitrite
        4. Peroxynitrite results in additional oxidative damage, especially within the liver

IV. Risk Factors: Serious to lethal hepatotoxicity

  1. Acetaminophen Overdosage
    1. Hepatoxic dose: >7.5 grams in <8 hours for adults (or >150 mg/kg in <8 hours for children)
    2. Acetaminophen is a common component in Analgesics and combination agents
  2. Chronic overdosage or repeat supratherapeutic doses
    1. Mortality is three-fold over the acute Acetaminophen overdosage
  3. Concurrent interacting factors: Lowers the threshold for N-Acetylcysteine use (baseline glutathione deficiency)
    1. Dehydration, Fasting or Malnutrition
    2. Alcohol Abuse
    3. Cirrhosis
    4. Concurrent use of other medications
      1. Isoniazid (reports of hepatotoxicity with concurrent Acetaminophen 3.2 grams)
      2. Zidovudine
      3. Barbiturate
      4. Phenytoin
      5. Acarbose

V. History

  1. Exact time of ingestion
  2. Acetaminophen formulation type
    1. Immediate release OR extended release
    2. Quantity of Acetaminophen taken
    3. Dosage or concentration of Acetaminophen
  3. Coingestions
    1. Aspirin
    2. Tricyclic Antidepressants
    3. Alcohol
    4. Opioids
    5. Benzodiazepines
  4. Psychiatric status
    1. Suicidal Ideation
    2. Psychosis

VI. Findings: Symptoms and Signs

  1. Anorexia
  2. Nausea and Vomiting
  3. Lethargy
  4. Elevated Liver Function Tests to Jaundice and liver failure
  5. Pallor

VII. Course: Stages

  1. Stage 1 (0 to 24 hours)
    1. Typically asymptomatic
    2. Nausea, Vomiting or general malaise may be present
    3. Normal Liver Function Tests
  2. Stage 2 (24 to 72 hours)
    1. Right upper quadrant pain
    2. Serum transaminases (AST, ALT) begin to rise
    3. Other markers may be elevated (Serum Bilirubin, PT/INR, PTT)
  3. Stage 3 (72 to 96 hours)
    1. Symptoms and signs are evident
      1. Jaundice
      2. Encephalopathy
    2. Severe lab abnormalities
      1. Liver Function Tests peak
      2. Coagulopathy
      3. Metabolic Acidosis with Anion Gap
      4. Acute Renal Failure may be present
      5. Acute Pancreatitis may be present
  4. Stage 4 (>96 hours)
    1. Patient either survives OR
    2. Fulminant liver failure, multiorgan failure and death

VIII. Labs

  1. General labs
    1. Bedside Glucose
    2. Serum Electrolytes with Renal Function tests (BUN, Serum Creatinine)
    3. Venous Blood Gas (VBG)
    4. Liver Function Tests
      1. Liver transaminases (AST, ALT)
        1. AST >1000 suggests severe hepatotoxicity (liver failure if encephalopathy present)
      2. Serum Bilirubin
      3. Serum Alkaline Phosphatase
      4. Serum Albumin and Serum Protein
    5. Coagulation tests
      1. INR/ProTime
      2. PTT
  2. Acetaminophen Level
    1. Precautions
      1. Nomogram cannot be used to interpret chronic or staggered ingestions
      2. Four hour level is most important (levels before that cannot be used to drive management)
      3. Recheck Acetaminophen level again at 8 hours if extended release formulation ingested
    2. Interpretation and treatment based on Rumack-Matthew Nomogram
      1. https://upload.wikimedia.org/wikipedia/commons/9/9b/Rumack_Matthew_nomogram_with_treatment_%28study%29_line.pdf
      2. Probable hepatotoxicity line
        1. Plasma Acetaminophen >200 mcg/ml at 4 hours
        2. Plasma Acetaminophen >6 mcg/ml at 24 hours
      3. Possible hepatotoxicity or treatment line (25% less than probable hepatotoxicity line)
        1. Plasma Acetaminophen >150 mcg/ml at 4 hours
        2. Plasma Acetaminophen >4.6 mcg/ml at 24 hours
    3. First level at 4 hours: >150 mcg/ml indicates treatment as below
      1. Concurrent interacting factors above lower the threshold for treatment
      2. UK now treats Acetaminophen levels >100 mcg/ml at 4 hours
    4. Consider obtaining an preliminary level at 2 hours (in addition to the 4 hour level)
      1. Acetaminophen level that is undetectable casts doubt on Acetaminophen Overdose
      2. Acetaminophen level <50 mcg/ml is reassuring
    5. Obtain second level at 8 hours if risk of delayed absorption (some recommend 12 hour level)
      1. Based on cases in which 4 hour level was below nomogram line, but 8 hour was above
      2. Co-ingestion of medication slowing GI motility or absorption
      3. Extended release Acetaminophen
      4. Acetaminophen with Diphenhydramine
      5. Acetaminophen with any Opioid
      6. Orman and Hayes in Herbert (2015) EM:RAP 15(3): 9-10
      7. Dougherty (2012) J Emerg Med 43: 58-63 +PMID:21719230 [PubMed]

IX. Management: General

  1. See Toxin Ingestion
  2. Obtain history as above
  3. Assess Airway, breathing and circulation
  4. Consider Activated Charcoal
    1. Indicated in presentation <1 hour from time of ingestion
    2. Limit to alert patients without aspiration risk
  5. Primary Antidote
    1. N-Acetylcysteine (NAC)
      1. First-line, primary management in all cases of Acetaminophen Toxicity (see indications below)
      2. Follow protocol as below
  6. Other Medications
    1. Fomepizole (4-methylpyrazole)
      1. Consider in late presentations of large Acetaminophen ingestion (>30 to 40 g)
      2. Primarily used in Toxic Alcohol ingestion (esp. Ethylene Glycol Poisoning)
      3. Discuss with Poison Control
      4. Dosing: 15 mg/kg load, then 10 mg/kg every 12 hours as needed
      5. Fomepizole is a CYP2E1 Inhibitor, preventing oxidative metabolite formation
      6. Fomepizole also blocks JNK activation, preventing further peroxynitrite formation
      7. Akakpo (2022) Arch Toxicol 96(2):453-65 +PMID: 34978586 [PubMed]

X. Management: N-Acetylcysteine (NAC)

  1. Indications
    1. Toxic Acetaminophen level (see above) OR
    2. Hepatoxic dose >7.5 grams in <8 hours for adults (or >150 mg/kg in <8 hours for children) OR
    3. Delayed presentation of known Acetaminophen ingestion
      1. Hepatotoxicity (AST or ALT>50 IU/L) OR
      2. Acetaminophen level >10 mcg/ml with timing of ingestion unclear
  2. Preparations
    1. Mucomyst oral or nebulized
    2. Acetadote intravenous
  3. Dosing
    1. See N-Acetylcysteine (Mucomyst)
    2. As directed by Rumack-Matthew Acetaminophen Nomogram (APAP Nomogram)
      1. http://www.ars-informatica.ca/toxicity_nomogram.php?calc=acetamin
      2. Based on 4 hour Acetaminophen level
      3. Consider a second Acetaminophen level at 8 hours if risk of delayed absorption (see above)
      4. Nomogram cannot be used to interpret chronic or staggered ingestions
  4. Protocol
    1. Initiate within 8 hours of ingestion (preferably at time of 4 hour level)
    2. Starting early (before the 4 hour level) does not improve outcomes
      1. Four hour level is most reliable and correlated to the APAP Nomogram
      2. Levels before 4 hours cannot adequately predict toxicity unless undetectable >1 hour post-ingestion
      3. Froberg (2013) Acad Emerg Med 20(10):1072-5 +PMID:24127715 [PubMed]
    3. Continue NAC beyond protocol if any of the following persist at end of protocol
      1. High Acetaminophen level or
      2. Increasing Bilirubin, INR or transaminases
  5. Duration
    1. Standard Course is 72 hours
      1. Used in nearly all U.S. cases
    2. Abbreviated course of 24 hours and until Acetaminophen level <10 mcg/ml
      1. Abbreviated course is not typically used in U.S.
      2. Appears safe and effective
      3. Woo (2000) Ann Emerg Med [PubMed]

XI. References

  1. Jackson (2023) Cri Dec Emerg Med 37(4): 32
  2. Orman and Hayes in Herbert (2016) EM:Rap 16(2): 2-3
  3. Podolsky, Shah and Campbell (2016) Crit Dec Emerg Med 30(6): 17-23
  4. Swencki (2015) Crit Dec Emerg Med 29(11):2-10

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