Basics
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 become 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 repeated supratherapeutic dosing.
Epidemiology
- Analgesics are the most common drugs implicated in poisoning exposures reported to U.S. poison control centers.
- Acetaminophen preparations make up ~45% of all analgesic poisoning exposures reported to poison control centers.
Incidence
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: alcoholism, isoniazid therapy, etc.
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.
- Proportionately more NAPQI is produced.
- Glutathione supply cannot meet detoxification demand.
- Hepatic or renal toxicity may ensue.
Etiology
- Single acute overdose of >150 mg/kg or 10 g
- Repeated overdose of >100 mg/kg/day or 6 g/day, for >2 days
Commonly Associated Conditions
- Acetaminophen is often marketed in combination with other pharmaceuticals, which may complicate a drug overdose situation.
- Adolescents frequently overdose on more than 1 drug preparation.
Diagnosis
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 <150 mg/kg (â¤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.
Diagnostic Tests & Interpretation
Lab
- Serum acetaminophen level
- Allows application of the Rumack-Matthew nomogram after acute overdose
- Rumack-Matthew nomogram applies only to single, acute acetaminophen overdose scenarios.
- Hepatic transaminases
- Aspartate aminotransferase (AST) is the most sensitive of the widely available measures to assess acetaminophen hepatotoxicity and begins to rise 12-24 hours after significant overdose.
- Liver and kidney function tests
- As the AST rises, it is important to follow liver and kidney function with tests such as serum glucose, prothrombin (PT) and partial thromboplastin (PTT) times, serum creatinine, plasma pH, and serum albumin.
- The PT and PTT may be slightly elevated owing to direct effect of elevated blood acetaminophen concentrations or N-acetylcysteine therapy, without signifying liver injury.
- The decline of an elevated serum AST may indicate either liver recovery or profound liver failure and must be interpreted in context.
- Salicylate level
- May be a coingestant in the setting of analgesic drug overdose
Pathologic Findings
Hepatic zone III (centrilobular) necrosis
Differential Diagnosis
- Infectious hepatitis
- Other drug-induced hepatitis
Treatment
Medication
First Line
- Single acute overdose
- Activated charcoal, 1-2 g/kg (maximum 75 g), may be administered if acetaminophen is judged to be present in the stomach or proximal intestine (usually within 1 hour of ingestion).
- N-acetylcysteine should be administered if a serum acetaminophen level obtained >4 hours after overdose falls above the treatment line of the Rumack-Matthew nomogram (see Appendix, Figure 4).
- Patients presenting to medical care >7 hours after overdose should be given a loading dose of N-acetylcysteine while waiting for the serum acetaminophen level result.
- Oral N-acetylcysteine dose: 140 mg/kg loading dose, followed by 70 mg/kg maintenance doses q4h (see "FAQ")
- Intravenous N-acetylcysteine dose: 150 mg/kg loading dose over 1 hour, then 12.5 mg/kg/h for 4 hours, then 6.25 mg/kg/h (see "FAQ").
- Repeated supratherapeutic ingestion
- Consider N-acetylcysteine therapy if
- Ingestion of >100 mg/kg or 6 g/day for consecutive days
- Patient is symptomatic
- AST level is elevated
- Acetaminophen level is higher than would be expected given dosing, and AST level is normal
- Once started, N-acetylcysteine therapy should be continued until
- The serum acetaminophen level is nondetectable
- A simultaneous serum AST has not risen or, if elevated, liver enzymes and liver function are clearly improving
Alert
- Some toxicologists suggest higher dosing for very large acetaminophen overdoses.
Second Line
- Acetaminophen poisoning and oral N-acetylcysteine therapy are emetogenic: chill and cover the N-acetylcysteine. Consider antiemetic therapy with drugs such as metoclopramide and/or ondansetron. Enteral N-acetylcysteine may be given slowly via nasogastric or nasoduodenal tube.
- Intravenous N-acetylcysteine has been associated with anaphylactoid reactions, which may require cessation or slowing of infusion, antihistamines, corticosteroids, and/or epinephrine.
Additional Treatment
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
Inpatient Considerations
Admission Criteria
- N-acetylcysteine therapy
- Psychiatric evaluation warranted
Discharge Criteria
- N-acetylcysteine therapy concluded
- No concern for developing liver injury
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Cardiorespiratory monitoring is warranted during intravenous N-acetylcysteine therapy.
- Intensive care monitoring is warranted during fulminant hepatic failure.
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 <150-200 mg/kg.
- After single acute acetaminophen overdose, likelihood of hepatotoxicity may be determined by using the Rumack-Matthew nomogram.
- N-acetylcysteine therapy prevents 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/day 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 intravenous N-acetylcysteine therapy.
Additional Reading
- Betten DP, Cantrell FL, Thomas SC, et al. A prospective evaluation of shortened course oral N-acetylcysteine for the treatment of acute acetaminophen poisoning. Ann Emerg Med. 2007;50(3):272-279. [View Abstract]
- Bronstein AC, Spyker DA, Cantilena LR, et al. 2011 annual report of the American Association of Poison Control Centers' National Poison Data System. Clin Toxicol. 2012;50(10):911-1164. [View Abstract]
- Chun LJ, Tong MJ, Busuttil RW, et al. Acetaminophen hepatotoxicity and acute liver failure. J Clin Gastroenterol. 2009;43(4):342-349. [View Abstract]
- Dart RC, Erdman AR, Olson KR, et al. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol. 2006;44(1):1-18. [View Abstract]
- Heard KJ. Acetylcysteine for acetaminophen poisoning. New Engl J Med. 2008;359(3):285-292. [View Abstract]
- Rumack BH, Bateman DN. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin Toxicol. 2012; 50(2):91-98. [View Abstract]
Codes
ICD09
- 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)
FAQ
- Q: What is "patient-tailored" N-acetylcysteine (NAC) therapy?
- A: The duration of N-acetylcysteine therapy used to depend on the pharmaceutical form administered but is now tailored to the patient based on serum acetaminophen level and liver function.
- Q: Should NAC be given PO or IV?
- A: Both seem to be similarly efficacious. Oral administration of NAC is complicated by taste aversion and vomiting. IV NAC may lead to anaphylactoid shock. Few cost-benefit studies are available for direct comparison of patient-tailored courses of oral NAC and IV NAC.