Description

• Acetaminophen poisoning may occur after acute or chronic overdose.
• Acetaminophen is sold under many brand names and is often an ingredient in combination pain reliever preparations.
• Acetaminophen poisoning may be clinically occult until frank hepatic or renal injury becomes evident.
• After acute overdose, a serum acetaminophen level above the treatment line of the Rumack-Matthew acetaminophen poisoning nomogram should be considered possibly hepatotoxic.
• Serious hepatotoxicity after a single acute exploratory ingestion by young children is rare compared with that from intentional overdose by adolescents.
• Most toddlers with acetaminophen hepatotoxicity suffer from repeated supratherapeutic dosing.

Epidemiology

• Analgesics are the most common drugs implicated in poisoning exposures reported to United States poison control centers.
• Acetaminophen preparations make up ~45% of all analgesic poisoning exposures reported to poison control centers.
• Acetaminophen poisoning is the most common cause of acute liver failure in the United States.

Risk Factors

• Depression
• Pain syndromes
• Glutathione depletion: prolonged vomiting, alcoholism, etc.
• CYP2E1 induction (e.g., alcoholism, isoniazid therapy)

General Prevention

• Acetaminophen should be stored with child-resistant caps, out of sight of young children.
• Proper use of acetaminophen products should be taught to patients with pain or fever.

Pathophysiology

• Most absorbed acetaminophen is metabolized through formation of hepatic glucuronide and sulfate conjugates.
• Some acetaminophen is metabolized by the CYP450 mixed-function oxidase system, leading to the formation of the toxic N-acetyl-p-benzoquinoneimine (NAPQI).
• NAPQI is quickly detoxified by glutathione under usual circumstances.
• After overdose, metabolic detoxification can become saturated:
  • Drug elimination half-life becomes prolonged.
  • More NAPQI is produced.
  • Glutathione supply cannot meet detoxification demand.
  • Hepatic or renal toxicity may ensue.

Etiology

• Single acute overdose of >200 mg/kg or 10 g
• Repeated overdose of >150 mg/kg/24 h or 6 g/24 h, for >2 days (or >100 mg/kg/24 h or 4 g/24 h if "susceptible")

Commonly Associated Conditions

• Acetaminophen is often marketed in combination with other pharmaceuticals, which may complicate a drug overdose situation.
• Adolescents frequently overdose on >1 drug preparation.

History

• Medical history of pain or fever
  • Acetaminophen ingestion should be explored in any patient being treated for pain or fever.
• Amount of acetaminophen ingested
  • A single, acute ingestion of <200 mg/kg (≤10 g in adolescents) is unlikely to cause significant toxicity among otherwise healthy individuals.
• Timing of ingestion
  • Allows application of the Rumack-Matthew nomogram
• Sustained-release preparation
  • Acetaminophen is now available in sustained-release form.
• Medication list
  • Use of isoniazid or other CYP2E1 hepatic enzyme inducers may increase risk for toxicity.
• Signs and symptoms
  • Initially may be clinically silent
  • Vomiting
  • Anorexia

Physical Exam

Right upper quadrant tenderness may suggest acetaminophen-induced hepatitis.

Differential Diagnosis

• Infectious hepatitis
• Other drug-induced hepatitis

General Measures

Evaluate for possible polypharmacy overdose.

Issues for Referral

• Patients with AST approaching 1,000 IU/L should be considered for transfer to a liver transplant center.
• Mental health services should be provided to victims of intentional overdose.

Surgery/Other Procedures

Liver transplant should be considered per transplant center protocols. The King's College Hospital Criteria include the following:

• pH <7.30 after resuscitation, or
• PT >1.8 times control, plus
• Serum creatinine >3.3 mg/dL, plus
• Encephalopathy

Admission, Inpatient, and Nursing Considerations

• Admission criteria
  • N-acetylcysteine therapy
  • Psychiatric evaluation warranted
• Discharge criteria
  • N-acetylcysteine therapy concluded
  • No concern for developing liver injury

Patient Education

• Drug administration education should be offered to victims of chronic overdose.
• Home safety education should be provided after pediatric exploratory ingestions.

Prognosis

• Among previously healthy children, hepatotoxicity is rare with single doses <150 to 200 mg/kg.
• After single acute acetaminophen overdose, likelihood of hepatotoxicity may be determined by using the Rumack-Matthew nomogram.
• N-Acetylcysteine therapy prevents fulminant hepatic failure in >99% of acetaminophen-poisoned patients if administered within 8 hours of overdose.
• N-Acetylcysteine therapy is less efficacious when administered >8 hours after overdose but should still be offered.
• Repetitive dosing of acetaminophen >75 mg/kg/24 h should be evaluated cautiously, especially in the presence of the following:
  • Febrile illness
  • Vomiting or malnourishment
  • Anticonvulsant or isoniazid therapy

Complications

• Hepatic failure
• Renal insufficiency
• Anaphylactoid shock may complicate IV N-acetylcysteine therapy.

ICD9

• 965.4 Poisoning by aromatic analgesics, not elsewhere classified
• 573.8 Other specified disorders of liver

ICD10

• T39.1X4A Poisoning by 4-Aminophenol derivatives, undetermined, init
• K71.9 Toxic liver disease, unspecified
• T39.1X1A Poisoning by 4-Aminophenol derivatives, accidental, init
• T39.1X2A Poisoning by 4-Aminophenol derivatives, self-harm, init

SNOMED

• 70273001 Poisoning by acetaminophen
• 197354009 toxic liver disease (disorder)
• 290134002 Accidental acetaminophen poisoning (disorder)
• 290136000 Acetaminophen poisoning of undetermined intent (disorder)