Acetaminophen overdose

Acetaminophen (APAP) is a non-opioid analgesic that can cause severe side effects when ingested in toxic amounts. Ingestion of ≤ 4 g/day of APAP is generally considered safe. APAP overdose is the leading cause of acute liver failure in the US and is commonly intentional. Clinical features, diagnostics, and management vary depending on the type of overdose, e.g., acute APAP overdose, massive APAP overdose, or chronic APAP overdose. In the early stages of acute APAP overdose, individuals may be asymptomatic or have nausea, vomiting, and lethargy. In later stages, individuals can develop signs of acute liver failure (ALF). Clinical features of chronic APAP overdose vary. Management is most often guided by serum APAP levels and other markers of liver function but can be empiric depending on the overdose type. The mainstay of therapy is the antidote N-acetylcysteine (NAC). Single-dose activated charcoal (AC) may be indicated for gastrointestinal decontamination. Patients with acute liver failure may require liver transplantation.

• Leading cause of acute liver failure ^[1][2]
• Acute APAP overdose has a mortality rate of < 0.5%. ^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Exhaustion of hepatic metabolic pathways causes accumulation of a toxic metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine (NAPQI). ^[1]
  • Glutathione initially inactivates NAPQI, but its reserves are eventually depleted, leading to NAPQI accumulation.
  • NAPQI → irreversible oxidative hepatocyte injury → liver cell necrosis
• APAP-induced hepatotoxicity
  • Defined as peak AST or ALT > 1000 IU/L
  • Most commonly caused by APAP overdose
  • Occurs rarely at therapeutic doses in patients with: ^[2]
    • Alcohol consumption
    • Prolonged fasting
    • Chronic liver disease ^[3]

Clinical features vary with the type of ingestion and the time since ingestion. Patients may be asymptomatic or have any of the following:

• Nausea, vomiting
• Pallor
• RUQ pain
• Signs of acute liver failure
• For specific types of ingestion:
  • See “Acute APAP overdose.”
  • See “Chronic APAP overdose.”

Serum APAP level ^[1][4]

• Indications
  • History or clinical features of APAP overdose
  • Elevated transaminases or ALF without apparent cause
  • Screening for APAP co-ingestion if poisoning by another substance is suspected
• Measurement and interpretation: depends on the time and acuity of ingestion
  • Detectability thresholds vary; be familiar with the cutoffs used at your institution. ^[5]
  • Acute ingestion
    • Interpret levels obtained 4–24 hours after ingestion. ^[1][4][6]
    • See “Serum APAP level in acute overdose” for details.
  • All other types of ingestion
    • A detectable level measured at any time is clinically significant.
    • See “Chronic APAP overdose” for details.

In acute APAP overdose, measure serum APAP levels at least 4 hours after ingestion, as levels measured prior to 4 hours are unreliable. ^[1][4][6]

Investigations for end-organ dysfunction ^[1]

• AST and ALT
  • Usually normal in the first 24 hours of acute APAP overdose
  • Normal or elevated in chronic APAP overdose
  • Can exceed 10,000 IU/L during maximal APAP-induced toxicity
• Coagulation studies: INR elevation can indicate ALF.
  • Serial measurements may be required (e.g., to identify NAC stopping criteria).
  • Avoid using PT alone to guide treatment or prognosis. ^[1]
• BMP: may show acute kidney injury (AKI)
• Blood gas analysis: may show metabolic acidosis
• Lactate: Elevated serum lactate after fluid resuscitation is associated with poor prognosis.

INR, PT, lactate, creatinine, and blood gas analysis are used in the King's College criteria to determine the need for liver transplantation. ^[7]

Screening for co-ingestions

Consider obtaining serum levels of commonly co-ingested substances, e.g.:

• Blood alcohol level
• Salicylate level

Patients may confuse aspirin, ibuprofen, and acetaminophen when providing history of an overdose. Consider screening for all detectable toxic OTC analgesics. ^[8]

• See “Common causes of severe elevation of transaminases.”
• See “Causes of acute liver failure.”
• See “Causes of altered mental status and coma.”
• See “Causes of nausea and vomiting.”
• See “Salicylate toxicity.”

The differential diagnoses listed here are not exhaustive.

Initial management ^[1][4][8]

• Follow the ABCDE approach for poisoning.
• Perform a toxicological risk assessment based on ingestion amount, type, and time.
• Obtain diagnostics for APAP overdose, e.g., serum APAP level, LFTs, BMP, VBG, and screening for co-ingestions.
• Administer single-dose AC and NAC therapy without delay, if indicated.
• Call poison control and consult a medical toxicologist; the US Poison Help line is 1-800-222-1222.
• Begin initial management of suicidal behavior, if indicated.

Obtain and interpret the serum APAP level based on the time and type of ingestion.

Approach ^[1][4][8]

Acute ingestion (< 24 hours)

See “Acute APAP overdose” for details.

• GI decontamination: single-dose AC if < 4 hours since ingestion; consider for extended-release (ER) APAP formulations ≥ 4 hours since ingestion.
• Antidote: Administer NAC based on serum APAP level ≥ 4 hours from ingestion and the Rumack-Matthew nomogram.

Massive ingestion

See “Massive APAP overdose” for details.

• Acute stabilization: Consider intubation and central venous line insertion.
• GI decontamination: single-dose AC indicated once the airway is protected
• Antidote: high-dose NAC indicated in consultation with medical toxicology
• Enhanced elimination: Consider hemodialysis in selected patients. ^[9]

Chronic ingestion, unknown time of ingestion, or > 24 hours since ingestion

See “Chronic APAP overdose” for details.

• GI decontamination: usually not indicated
• Antidote: Consider NAC based on clinical evaluation, serum APAP level at presentation, and LFTs, in consultation with a toxicologist.

Definitive treatment

• Antidote: PO or IV N-acetylcysteine (NAC) is used to treat and prevent APAP-induced hepatoxicity.
  • Specific indications
    • See “Acute APAP overdose.”
    • See “Chronic APAP overdose.”
  • Dosage and administration: See “NAC for APAP overdose.”
• Liver transplant: indicated for selected patients with acute liver failure
  • Identify candidates using King's College criteria.
  • See “Management of ALF” for pre-transplant management.

Monitoring ^[1][8]

Laboratory monitoring is indicated to assess treatment efficacy and identify NAC stopping criteria, liver transplant candidates, and complications.

• Normal initial AST: Repeat AST before the end of the treatment protocol or every 24 hours.
• Elevated initial AST: Monitor PT, INR, and creatinine levels at least daily.
• Signs of liver failure and/or extrahepatic organ toxicity: Monitor pH, lactate, and phosphate.
• ER formulations of APAP or co-ingestion of medications that delay GI transit (e.g., opioids, anticholinergics): Consider repeat serum APAP levels in consultation with a toxicologist.

Disposition ^[1][8]

• Signs of liver failure: Admit to monitored bed or critical care based on clinical status and monitoring needs.
• Asymptomatic or stable on NAC treatment: Admit to inpatient or observation unit.
• Asymptomatic, no NAC required, and normal or baseline AST: Assess if further medical treatment is necessary; consider further disposition based on suicidal risk or risk of self-harm.
• Suicidality suspected
  • Consult psychiatry.
  • Admit patients with high suicidal risk to hospital even if medically stable; involuntary commitment may be necessary.

Mechanism of action ^[1][10]

• Replenishes glutathione stores in the liver ^[1][10]
• Close to 100% effective in preventing hepatotoxicity if administered within 8 hours of ingestion ^[1]

Indications ^[1][4][8]

• Acetaminophen toxicity
  • Acute ingestion
    • Serum concentration of APAP above the treatment line on the Rumack-Matthew nomogram
    • Empiric administration: if ingestion is ≥ 30 g or APAP level cannot be obtained within 8 hours of ingestion ^[4]
  • Chronic ingestion: serum APAP level > 10 mcg/mL and/or AST or ALT above baseline
  • Unknown time of ingestion: serum APAP level detectable and/or AST or ALT above baseline
• Less common indications
  • Mucolysis: e.g., in patients with COPD, chronic bronchitis, intubated patients
  • Off-label for hepatotoxicity associated with oxidative injury, e.g.: ^[1]
    • Amatoxin (Amanita phalloides poisoning)
    • Carbon tetrachloride poisoning
    • Consider for other causes of drug-induced liver injury. ^[2]

Contraindications ^[4]

• There are no contraindications.
• A previous anaphylactoid reaction is not a contraindication to NAC for APAP overdose.

NAC for APAP overdose ^[1][4]

There is no gold standard regimen for NAC administration. Follow local protocols and consult poison control if needed.

• In acute APAP overdose, initiate therapy as soon as possible at least 4 hours after ingestion; ideally within 8 hours of ingestion.
• Select a protocol that delivers at least 300 mg/kg PO or IV in the first 20–24 hours, e.g.: ^[4]
  • Standard IV NAC protocol (“three-bag method”) ^[1][2][4]
  • Oral NAC protocol ^[1][2][4]
  • Discuss further doses with a toxicologist.
• Measure serum APAP and AST prior to completion of the IV infusion or at 24 hours for PO NAC.
• Continue until NAC stopping criteria are met. ^[4][5]

Avoid oral NAC administration in patients with potential airway compromise.

NAC stopping criteria ^[1][4]

All of the following must be present:

• Serum APAP level undetectable
• INR < 2.0
• ALT and AST at baseline or 25–50% below peak
• Patient clinically well

Adverse effects ^[4]

• Nausea, vomiting
• Anaphylactoid reaction

Definition

• A large ingestion or multiple ingestions over a brief period of time, usually < 24 hours ^[1][4]
• Minimum toxic dose ^[1][4]
  • Healthy adults: 7.5 g/day
  • Children: 150 mg/kg/day

Ingestions occurring > 24 hours or at an unknown time before presentation, even large single ones, are typically managed as chronic APAP overdoses. ^[4]

Stages of acute APAP toxicity ^[1][8][11]

Clinical and biochemical findings vary depending on the amount ingested and the time from ingestion.

• Stage 1: first 24 hours after ingestion
  • Most patients are asymptomatic.
  • Nonspecific symptoms: nausea, vomiting, pallor
  • Normal liver chemistries
• Stage 2: 24–36 hours after ingestion
  • Nausea, vomiting, RUQ pain
  • Abnormal liver chemistries
• Stage 3: 72–96 hours after ingestion
  • Time of maximal liver toxicity and highest likelihood of death
  • Progressive liver impairment: signs of ALF
  • Hemorrhage due to ALF-induced coagulopathy (see “Clinical features of bleeding disorders”)
  • AKI occurs in up to 25% of patients with significant liver toxicity.
• Stage 4: recovery phase
  • AST, pH, lactate, and coagulation studies usually normalize within 7 days.
  • ALT and creatinine may remain elevated for longer.

Coma, metabolic acidosis, and death can occur during the first stage of a massive APAP overdose.

Diagnostics ^[1][4]

• Obtain diagnostics for APAP overdose.
• Serum APAP level in acute overdose
  • < 2 hours from ingestion: Do not interpret; retake level 4 hours after ingestion.
  • 2–4 hours from ingestion
    • If APAP is undetectable: Acute toxicity is unlikely.
    • If APAP is detected: Do not interpret; retake level 4 hours after ingestion.
  • 4–24 hours from ingestion
    • Obtain level immediately.
    • Interpret using the Rumack-Matthew nomogram.
    • ER formulations or co-ingestion with opioids and/or anticholinergics
      • APAP level < 10 mcg/mL: no further measurement needed
      • APAP level > 10 mcg/mL and lower than treatment line: Repeat level 4–6 hours after the initial measurement.

Rumack-Matthew nomogram ^[1]

• A graph used to determine the risk of severe hepatotoxicity in acute APAP overdose based on:
  • Serum APAP level obtained 4–24 hours after ingestion
  • Time since ingestion
• NAC is indicated if the serum APAP level is above the treatment line.

Do not use the Rumack-Matthew nomogram if < 4 hours or > 24 hours have passed since ingestion, or if the time of ingestion is unreliable or unknown. ^[4]

Management ^[1][2][12]

• GI decontamination
  • Any formulation < 4 hours from ingestion: Administer single-dose AC unless contraindicated.
  • ER formulation ≥ 4 hours after ingestion: Consider single-dose AC. ^[4]
• Antidote: NAC
  • Indication: serum APAP level measured ≥ 4 hours from ingestion that is above the Rumack-Matthew nomogram treatment line
  • Dosage and administration: See “NAC protocol.”
• Supportive care, monitoring, and disposition: See “Management of APAP overdose.”

Massive APAP overdose ^[1][8][11]

• Definition: ingestion of ≥ 30–40 g or > 0.5 g/kg body weight ^[4][8][13]
• Clinical features
  • Early altered mental status or coma
  • Other clinical features of acute APAP overdose, e.g., signs of ALF
• Diagnostics
  • Early lactic acidosis
  • Diagnostic findings of ALF
• Management ^[4]
  • Follow the ABCDE approach for poisoning.
  • Consult toxicology and nephrology for hemodialysis. ^[8][9]
  • Consider single-dose AC regardless of time from ingestion.
  • Begin NAC; consider a higher dosage than standard in consultation with a toxicologist.
  • Admit patients to the ICU for ongoing management of ALF.

Patients with massive APAP overdose may require intubation for airway protection and central venous line insertion for hemodialysis.

The following checklist pertains to acute APAP toxicity.

• Follow the ABCDE approach.
• Determine ingestion time and amount, if possible.
• Consult poison control.
• For massive APAP overdoses:
  • Consider intubation for airway protection.
  • Consider single-dose AC (via NG tube) regardless of time from ingestion.
  • Administer NAC empirically.
  • Insert CVL as needed for hemodialysis.
• Order diagnostics for APAP overdose.
• < 4 hours post-ingestion
  • Administer single-dose AC.
  • Wait until 4 hours post-ingestion and obtain APAP level.
• 4–24 hours post-ingestion: Measure APAP level and administer NAC based on the Rumack-Matthew nomogram.
• > 24 hours post-ingestion: Administer NAC if APAP level is detectable or AST is above patient's baseline.
• Obtain consults.
  • Nephrology for hemodialysis if massive APAP overdose
  • Transplant surgery if King's College criteria are met
  • Psychiatry if history of intentional overdose reported or suicidality suspected
• Admit to hospital if NAC is required.
• Consider ICU admission if ALF is present.
• Consider discharge for asymptomatic patients who do not require NAC and have no ongoing suicidal risk.

Single ingestions occurring > 24 hours or at an unknown time before presentation are typically managed as chronic APAP overdoses. ^[4]

Chronic APAP overdose

• Repeated supratherapeutic ingestion over a period of > 24 hours ^[4]
• Minimum toxic dose for healthy adults and children if ingested over the following periods: ^[4]
  • 24–48 hours: 6 g/day or 150 mg/kg/day (whichever is less)
  • > 48 hours: 4 g/day or 100 mg/kg/day (whichever is less)

Clinical features ^[1]

• Patients may be asymptomatic or have one or more clinical features of APAP toxicity.
• Signs of liver failure may be present.

Diagnostics

• Obtain a collateral history from family or caregivers.
• Order diagnostics for APAP overdose.
• Measure and interpret serum APAP level as soon as possible.

Do not use the Rumack-Matthew nomogram to estimate hepatotoxicity risk for chronic APAP overdose, unknown time of ingestion, or single ingestions > 24 hours before presentation.

Management

Guidance for chronic APAP overdose is not well established. ^[1]

• Begin initial management of APAP overdose in consultation with a medical toxicologist.
• GI decontamination is typically not useful.
• Estimate hepatotoxicity based on serum APAP level, AST level, and individual risk factors.
• Repeat APAP levels as indicated after initiating treatment to determine if NAC stopping criteria have been met.
• Supportive care, monitoring, and disposition: See “Management of APAP overdose.”

NAC

• Indications
  • AST elevated or above the patient's baseline
  • Chronic APAP overdose: serum APAP level > 20 mcg/mL ^[4]
  • Unknown ingestion time: detectable serum APAP level
• Administration
  • Initiate NAC for APAP overdose.
  • Discuss further dosages with a medical toxicologist.
  • Continue until NAC stopping criteria are met.

If in doubt of the timing or severity of APAP ingestion, administer NAC empirically, as the benefits significantly outweigh the risks. ^[4]