Acetaminophen Overdose

Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Because APAP is primarily metabolized by the liver, overdose can lead to life threatening hepatotoxicity. In adults, limitation of total APAP dose (from all sources and routes) to < 4,000 mg per day is recommended. During evaluation, a thorough history and measurement of serum APAP are important, as the initial clinical stages of APAP overdose can be nonspecific. Management of overdose includes drug serum concentration, stabilization, decontamination, and administration of N-acetylcysteine (NAC). Use of NAC within 8 hours of ingestion is associated with good case outcomes. Without treatment, however, cases are at significant risk of severe hepatotoxicity and potentially death.

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Epidemiology

  • Most common cause of acute liver failure (ALF) in the United States
  • At-risk populations:
    • Limited literacy
    • Heavy APAP use
    • APAP/opioid combination use
  • Significant number of overdoses are unintentional:
    • Failure to recognize APAP contents in medication
    • Incorrect understanding of dosing directions
  • Early identification of overdose is associated with low mortality rates.
  • Development of ALF:
    • Associated with 28% mortality
    • One third of cases with ALF require liver transplantation.

Pathophysiology

Pharmacokinetics

  • APAP is quickly absorbed via the GI tract.
  • Therapeutic dose serum concentrations peak after 0.5–2 hours.
  • In overdose:
    • Serum concentrations peak within 4 hours.
    • Can be > 4 hours if taken with drugs that delay gastric emptying
  • Therapeutic dose:
    • Children: 10–15 mg/kg every 4–6 hours
    • Adults: 325–1,000 mg every 4–6 hours (maximum: 4 g a day)
  • Toxic dose (single ingestion):
    • > 250 mg/kg or > 12 g over a 24-hour period
    • Note: lower dose threshold for alcoholics/anticonvulsant users
    • Ingestion of > 350 mg/kg likely to result in severe livery toxicity if untreated
    • Severe livery toxicity: peak AST or ALT > 1,000 IU/L

Normal metabolism

  • About 90% is metabolized in the liver to sulfate and glucuronide → excreted in urine
  • Remaining undergoes oxidation via hepatic cytochrome P450 (primarily CYP2E1)
    • CYP2E1 pathway produces the toxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI).
    • NAPQI is normally detoxified by glutathione → nontoxic cysteine and mercaptate compounds → excreted in urine

Pathogenesis

  • At therapeutic doses of APAP:
    • NAPQI pathway is relatively underutilized. 
    • NAPQI metabolites are rapidly conjugated to nontoxic compounds.
  • At toxic doses: 
    • Primary hepatic metabolism pathways become oversaturated.
    • ↑ APAP metabolism via cytochrome P450 → ↑ NAPQI production
    • ↑ NAPQI depletes glutathione levels and saturate the elimination pathways
    • ↑ Free NAPQI binds with hepatic macromolecules → produce NAPQI-protein adducts (irreversible process) → ↑ oxidative stress → hepatocellular necrosis

Clinical Presentation

The clinical course of APAP poisoning is often divided into 4 stages that are classified according to duration since time of ingestion.

  • Stage I (first 24 hours)
    • Nausea and vomiting, malaise
    • May be asymptomatic
    • Laboratory studies are usually normal.
  • Stage II (24–72 hours)
    • Ongoing hepatic necrosis results in ↑ transaminases by 36 hours
    • RUQ pain and hepatomegaly occur.
    • ↑ Prothrombin time (PT) and total bilirubin, oliguria, and abnormal creatinine may occur
  • Stage III (72–96 hours)
    • Liver function abnormalities peak.
    • Stage I symptoms return with jaundice, confusion, and bleeding diathesis.
    • Severe hepatotoxicity: 
      • ALT, AST > 10,000 IU/L
      • Prolonged PT/INR
      • Lactic acidosis
      • Bilirubin > 4 mg/dL
    • Possibly complicated with ALF, renal failure, and pancreatitis
    • Death often occurs due to multiorgan failure.
  • Stage IV (4 days to 2 weeks):
    • If stage III is survived, cases enter a recovery phase.
    • Recovery is typically complete by week 1 (longer if severely ill).
    • Symptoms and laboratory values can take weeks to return to normal.

Diagnosis

Evaluation

  • Obtain a thorough history: intent, dose, time of ingestion, coingestants, and comorbidities.
  • Serum APAP concentration (sAPAP) is the basis for diagnosis.
    • Should be measured in every case
    • Draw 4 hours after time of ingestion (levels < 4 hours may not be indicative of peak values).
    • If time of ingestion > 4 hours or unknown → immediate sAPAP → repeat in 4 hours
    • If initial sAPAP undetectable → observe individual and repeat sAPAP in 4 hours
  • Time of ingestion and sAPAP are the best predictors of hepatotoxicity.
  • If toxicity confirmed or predicted, additional tests should be ordered:
    • Chemistry panel
    • LFTs
    • PT/INR
    • Urinalysis

Rumack-Matthew nomogram

  • Guides the use of the antidote N-acetylcysteine (NAC) based on sAPAP and hours since ingestion in relation to probability of hepatotoxicity
  • Cases that lie above the treatment line are treated with NAC.
  • Cannot be used for ingestion that occurred > 24 hours prior to presentation, repeated elevated doses, intravenous overdose, or sustained release dose
Rumack Matthew nomogram Acetaminophen Overdose

Rumack-Matthew nomogram (acetaminophen toxicity nomogram):
Used after a single acute acetaminophen ingestion.
The nomogram predicts potential hepatotoxicity beginning at 4 hours after ingestion. Levels measured earlier than 4 hours may not be reliable.
The nomogram cannot be used for ingestions that occurred > 24 hours prior to presentation.

The upper (red) line is the Rumack-Matthew line; values above this line develop toxicity (noted in 60%).
The lower (blue) line is the treatment line (U.S. Food and Drug Administration required treatment line to be 25% below the original line).

NAC treatment is given when the acetaminophen level is at the treatment line 4 hours post ingestion (which is below the toxicity threshold).

Image by Lecturio.

Management

Treatment approach

Entails supportive care, limiting drug absorption, and treatment of toxic effects:

  • Initial management: secure airway, breathing, and circulation
  • GI decontamination: activated charcoal to all adults presenting within 4 hours of ingestion
    • More effective than induced emesis and gastric lavage
    • Do not give if individual is sedated or unable to manage their airway.
Treatment algorithm for acetaminophen

Overview of the treatment algorithm for acetaminophen toxicity

Image by Lecturio.

N-acetylcysteine (NAC)

  • Antidote for APAP, given to all individuals at risk for hepatotoxicity
  • Repletes glutathione stores and subsequently decreases NAPQI production
  • Indications for NAC: 
    • History of APAP ingestion and evidence of any liver injury
    • sAPAP (drawn at ≥ 4 hours) above nomogram treatment line
    • Unclear time of ingestion and serum drug level of > 10 µg/mL
    • Suspected single dose of > 7.5 g or 150 mg/kg (if sAPAP unavailable > 8 hours after ingestion)
    • > 24 hours after ingestion with evidence of liver injury
  • If given within 8 hours, serious hepatotoxicity is prevented and death is rare.
  • Treatment protocol and duration:
    • Can vary based on individual case and clinical judgment
    • Cases are generally treated for 20–72 hours.
  • Available in oral and IV forms
    • In general, both are acceptable. 
    • Use IV for:
      • Cases with intractable vomiting
      • Hepatic failure
      • Contraindications to oral: pancreatitis, ileus, bowel obstruction/injury
  • Adverse reactions:
    • Anaphylaxis: 10%–20% develop a hypersensitivity reaction.
    • Vomiting: About 33% of cases develop nausea and vomiting.
      • If vomiting occurs ≤ 1 hour after NAC administration → repeat dose
      • If vomiting persistent → administer IV formation

References

  1. Burns, M. J., Friedman, S. L. & Larson, A. M. (2021). Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation. UpToDate. Retrieved July 30, 2021, from https://www.uptodate.com/contents/acetaminophen-paracetamol-poisoning-in-adults-pathophysiology-presentation-and-evaluation
  2. Heard, K. & Dart, R. (2021). Acetaminophen (paracetamol) poisoning in adults: Treatment. UpToDate. Retrieved July 30, 2021, from https://www.uptodate.com/contents/acetaminophen-paracetamol-poisoning-in-adults
  3. Ghanem, C. I., Pérez, M. J., Manautou, J. E. & Mottino, A. D. (2016). Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity. Pharmacol Res 109, 119–131.

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