ACETAMINOPHEN POISONING

ACETAMINOPHEN POISONING - Lars C. Larsen, MD
BASICS
DESCRIPTION
• A disorder characterized by hepatic necrosis following large ingestions of acetaminophen. Symptoms may vary from initial nausea, vomiting, diaphoresis, and malaise to jaundice, confusion, somnolence, coma, and death. The clinical hallmark is the onset of symptoms within 24 hours of ingestion of acetaminophen-only or -combination products.
• Acetaminophen poisoning is most often encountered following large single ingestions of acetaminophen-containing medications. Usual toxic doses are >7.5 g in adults and 150 mg/kg in children. However, poisoning also occurs after acute and chronic ingestions of lesser amounts in susceptible individuals, including those who regularly abuse alcohol, are chronically malnourished, or take medications that affect hepatic metabolism of acetaminophen.
• Therapeutic adult doses are 0.5-1 q4-6h; up to a maximum of 4 g/d. Therapeutic pediatric doses are 10-15 mg/kg q4-6h, not to exceed 5 doses in 24 hours.
• System(s) Affected: Cardiovascular; Gastrointestinal; Renal/Urologic
• Synonym(s): Paracetamol poisoning
ALERT
Geriatric Considerations
Hepatic damage may be increased if taking hepatotoxic medications chronically.
Pediatric Considerations
Hepatic damage at toxic acetaminophen levels is decreased in children 6 years.
Pregnancy Considerations
• Increased incidence of spontaneous abortion, especially with overdose at early gestational age
• Incidence of spontaneous abortion or fetal death appears to be increased when N-acetylcysteine (NAC) treatment is delayed.
GENERAL PREVENTION
Parent/caregiver education essential:
• Education during well child exams regarding poisoning prevention
• Emergency telephone numbers
EPIDEMIOLOGY
• Predominant age: Children and adults at any age
• Predominant sex: No reported association
Incidence
• >131,700 ingestions of acetaminophen containing medications reported by poison control centers in 2004
• 327 deaths in 2004, 3 in children 6 years
Prevalence
Approximately 31% of exposures are in children 6 years.
RISK FACTORS
• Age 6 years
• Concurrent oral poisoning with other substances
• Psychiatric illness
• History of previous toxic ingestions or suicide attempts
• Regular ingestion of large amounts of alcohol
ETIOLOGY
Accidental or intentional ingestion of acetaminophen or combination medications containing acetaminophen


DIAGNOSIS
SIGNS AND SYMPTOMS
• Develop over the 1st 24 hours following large ingestions and may last as long as 8 days
• Severe symptoms indicate large ingestions or coingestants
• Fulminant hepatic failure occurs in 1% of adults and is very rare in children 6 years.
• Stage 1: 1st 24 hours
- Nausea
- Vomiting
- Diaphoresis
• Stage 2: 24-48 hours
- Right upper quadrant pain
- Typically less nausea, vomiting, diaphoresis, and malaise than in stage 1
• Stage 3: 72-96 hours
- Nausea, vomiting, malaise reappear
- Severe poisonings may result in jaundice, confusion, somnolence, and coma
• Stage 4: 7-8 days
- Resolution of clinical signs in survivors
• May develop gradually following long-term ingestion of near-therapeutic amounts of acetaminophen. Such patients may present in any stage 1-3, without a history of ingestion of the usual toxic doses.
TESTS
Lab
• Plasma acetaminophen levels should be drawn on all patients 4 hours or more after ingestion (levels prior to 4 hours not helpful).
• At least one additional acetaminophen level drawn 4-6 hours after the 1st level is recommended if the ingested acetaminophen is an extended-release product (e.g., Tylenol Extended Relief) or is not known to be an immediate-release product.
• If the second level is >1st level or is close to the "possible risk" level on the Rumack-Matthew nomogram, it may be prudent to obtain additional acetaminophen levels every 2 hours until the levels stabilize or decline.
• If coingestants include drugs that slow gastrointestinal motility, an acetaminophen level drawn 4-6 hours after the 2nd level may detect a late increase in serum acetaminophen concentration.
• Screens for suspected coingestants (aspirin, iron, and others) may be positive (especially when suicide is a possibility).
• With toxic ingestions, aspartate transaminase (AST; serum glutamic-oxaloacetic transaminase), alanine transaminase (serum glutamic-pyruvic transaminase), and bilirubin levels begin to rise in stage 2 and peak in stage 3. In severe poisonings, the prothrombin time will parallel these changes.
• AST levels >1,000 IU/L are consistent with the diagnosis, and levels of 20,000 IU/L are not uncommon.
• Laboratory abnormalities usually resolve by stage 4.
• Renal function abnormalities are common in patients with hepatotoxicity.
• Evidence of damage to the pancreas and heart may present following severe poisonings.
• Drugs that may alter lab results: None with clinically significant cross-reactivity with plasma acetaminophen assay
• Disorders that may alter lab results: Diseases or toxic substances that damage the liver, particularly alcohol
Imaging
No specific imaging required
Diagnostic Procedures/Surgery
None other than correlating plasma acetaminophen levels with the clinical presentation
Pathological Findings
Centrilobular hepatic necrosis
DIFFERENTIAL DIAGNOSIS
• Consider presence of coingestants, especially alcohol
• Other ingested toxins that produce severe acute hepatic injury, including the mushroom Amanita phalloides and products containing yellow phosphorus or carbon tetrachloride
TREATMENT
STABILIZATION
Contact a regional poison control center for management recommendations. In the United States, a local poison control center can be reached by calling (800) 222-1222.
GENERAL MEASURES
• Activated charcoal should be used (1,2)[C]; (3)[A], but preferably not within 1 hour of administration of the antidote NAC.
• The stomach of untreated patients may be emptied by gastric lavage if within 1 hour of ingestion.
• Ipecac is no longer recommended for routine use at home or in health care facilities (4)[C].
• NAC should be given (3)[A] when plasma acetaminophen concentrations measured 4 hours or more after ingestion are in the "possible risk" or higher levels on the Rumack-Matthew nomogram. This corresponds to acetaminophen levels >150 ug/mL (993 umol/L), >75 ug/mL (497 umol/L), and >40 ug/mL (265 umol/L) at 4, 8, and 12 hours after ingestion, respectively.
• NAC therapy may be effective up to 36 hours or more after ingestion
Diet
No special diet except with severe hepatic damage
Activity
Restricted if significant hepatic damage has occurred
MEDICATION (DRUGS)
First Line
• 2 classes of medicine
- Activated charcoal
- Acetylcysteine (NAC, Mucomyst)
• Emergency facility/hospital
- Patients evaluated within 1 hour of ingestion may have their stomachs evacuated by gastric lavage.
- Activated charcoal: 1 g/kg PO for initial dose; preferably not within 1 hour of NAC administration. Additional concurrent use during NAC therapy is controversial.
- Acetylcysteine PO or IV
 Oral loading dose of 140 mg/kg, followed by 70 mg/kg q4h for 17 additional doses. Whenever possible, NAC therapy should be initiated within 8 hours following the toxic ingestion.
 IV loading dose of Acetadote 150 mg/kg over 15 minutes X 1 (some recommend the loading dose be given over 60 minutes to decrease incidence of anaphylactoid rxns). Maintenance doses: 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours.
• Contraindications: Medication allergies
• Precautions
- Oral NAC may cause significant nausea and vomiting due to its sulfur content; consider administration by nasogastric tube.
- Nausea can be treated with metoclopramide (Reglan), 0.5-1 mg/kg IV, or ondansetron (Zofran), 0.15 mg/kg IV (for age >4 years, usually 4 mg/dose).
- IV NAC (Acetadote) may cause anaphylactoid rxns including rash, bronchospasm, pruritis, angioedema, tachycardia, or hypotension.
• Reactions usually occur with loading dose. Slow or temporarily stop the infusion; may concurrently treat with antihistamines
• Significant possible interactions: Activated charcoal given within 1 hour of NAC may adsorb the NAC, thereby limiting its effectiveness.
Second Line
Oral racemethionine (methionine)
FOLLOW-UP
DISPOSITION
• All patients should be evaluated at a health care facility.
• Outpatient for nontoxic accidental ingestions
Admission Criteria
Toxic and intentional ingestions
Issues for Referral
Psychiatric follow-up after intentional ingestions
PROGNOSIS
• Complete recovery with early therapy
• 1% of adult patients develop hepatic failure.
• Hepatic failure is very rare in children 6 years.
COMPLICATIONS
Rare following recovery from acute poisoning
REFERENCES
1. Gaudreault P. Activated charcoal revisited. Clin Ped Emerg Med. 2005;6:76-80.
2. Heard K. Gastric Decontamination. Med Clin N Am. 2005;89:1067-1078.
3. Brok J, Buckley N, Glud C. Interventions for paracetamol (acetaminophen) overdoses. The Cochrane Database of Systematic Reviews. 2006; volume 1.
4. American Academy of Pediatrics Committee on Injury, Violence, and Poison Prevention. Poison treatment in the home. Pediatrics. 2003;112:1182-1185.
5. Acetylcysteine (Acetadote) for acetaminophen overdosage. The Medical Letter 2005;47:70-71.
6. Watson WA, Litovitz TL, Rodgers GC Jr, et al. 2004 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Amer J Emerg Med. 2005;23(pt 5)1: 589-666.