Acetaminophen Poisoning

Acetaminophen Poisoning

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 above 10 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 g q4–6h, up to a maximum of 4 g/d. Therapeutic pediatric doses are 10–20 mg/kg q4–6h.
• System(s) affected: Gastrointestinal; Cardiovascular; Renal/Urologic:
  • Multisystem organ failure can occur.
• Synonym(s): Paracetamol poisoning

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.
• The optimal route for administration of NAC in pregnant patients remains debatable, although IV NAC may offer greater bioavailability.

Epidemiology

• Predominant age: Children and adults
• Predominant sex: No reported association

Incidence

• More than 50,000 calls placed to poison control centers in 2007 related to possible acetaminophen overdoses.
• 74 deaths in 2006, none in children <6 years of age

Prevalence

Approximately 29% of single exposures are in children <6 years.

Risk Factors

• Age >6 years
• Concurrent poisoning with other substances
• Psychiatric illness
• Previous toxic ingestions or suicide attempts
• Regular ingestion of large amounts of alcohol

General Prevention

Parent/caregiver education essential:

• Education during well-child exams regarding poisoning prevention
• Emergency telephone numbers

Etiology

• Accidental or intentional ingestion of acetaminophen or combination medications containing acetaminophen
• Approximately 96% of ingested acetaminophen is metabolized in the liver with only 2% to 4% excreted unchanged in the urine. When taken in therapeutic doses, 90–95% of hepatic metabolism occurs via glucuronidation and sulfation and results in the formation of benign metabolites. 5–10% of hepatic metabolism is by oxidation through the cytochrome P₄₅₀ enzyme system (CYP 3A4 and CYP 2E1) and results in the formation of the toxic metabolite N-acetyl-p-benzoquinoneimne (NAPQI). NAPQI is rapidly conjugated with glutathione to form a nontoxic metabolite. The metabolites are excreted in the urine along with the small amount of unchanged drug. Hepatocellular damage typically occurs when toxic doses of acetaminophen result in saturation of the glucuronidation and sulfation pathways with subsequent production of excessive amounts of NAPQI. Available glutathione stores become depleted, NAPQI accumulates, and hepatocellular damage occurs.

Diagnosis

• Signs and symptoms develop over the 1st 24 hours following large ingestions, and may last as long as 8 days.
• May develop gradually following long-term ingestion of near maximal-therapeutic amounts of acetaminophen. Such patients may present in stages 1–3, without a history of ingestion of the usual toxic doses.
• Severe symptoms indicate large ingestions or coingestants:
  • Stage 1: 1st 24 hours after time of ingestion:
    • 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
• Fulminant hepatic failure occurs in <1% of adults and is very rare in children <6 years of age.
• Patients with an unexplained rise in liver function tests (LFTs) with negative acetaminophen levels may be overdose patients presenting in stage 3.

History

Ingestion or suspected ingestion of acetaminophen-containing product

Diagnostic Tests & Interpretation

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 1 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 2nd level is higher than the 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 (GI) 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 attempt is a possibility).
• With toxic ingestions, aspartate transaminase (AST; serum glutamic-oxaloacetic transaminase), alanine transaminase (ALT; serum glutamic-pyruvic transaminase), and bilirubin levels begin to rise in stage 2 and peak in stage 3. In severe poisonings, the PT/INR will parallel these changes and should be monitored.
• 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.

Initial lab tests

• Acetaminophen serum concentration: 4 hours after ingestion and again per comments above (see General)
• AST, ALT (rise in first 72 hours, then slowly decline), prothrombin time (PT)/international normalized ration (INR), bilirubin, LDH
• Electrolytes, glucose, blood urea nitrogen (BUN), creatinine
• Pregnancy screen in females (urine or serum)
• Urinalysis
• Consider arterial blood gas if pH disturbance suspected on clinical or lab grounds.

Follow-Up & Special Considerations

• Repeat 4 hours after ingestion and possibly every 2 hours thereafter if long-acting product is ingested or acetaminophen ingested with other agents that slow GI passage.
• Arterial blood gas after hydration if pH is acidotic

Imaging

No specific imaging required

Pathological Findings

Centrilobular hepatic necrosis

Differential Diagnosis

• Consider presence of coingestants, especially alcohol and aspirin.
• Other ingested toxins that produce severe acute hepatic injury, including the mushroom Amanita phalloides and products containing yellow phosphorus or carbon tetrachloride

Treatment

• Contact a regional poison control center for management recommendations. In the US, a local poison control center can be reached by calling (800) 222-1222.
• NAC should be given 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 µg/mL (993 µmol/L), >75 µg/mL (497 µmol/L), and >37 µg/mL (244 µmol/L) at 4, 8, and 12 hours after ingestion, respectively. See http://www.ars-informatica.ca/toxicity_nomogram.php?calc = acetamin or http://www.merck.com/mmpe/sec21/ch326/ch326c.html
• NAC should be started within 8 hours of ingestion for best chance of hepatic protection. Patients presenting near 8 hours should empirically receive NAC while waiting for labs.
• All patients with acetaminophen liver injury (even after 8 hours) should receive NAC.
• NAC therapy may be effective up to 36 hours or more after ingestion.
• Single dose activated charcoal can be used (especially in cases of coingestants) (1,2)[C],(3)[A] but not within 1 hour of administration of the antidote NAC. Never delay NAC for activated charcoal.
• NAC should be initiated within 8 hours of ingestion whenever possible.
• Ipecac and gastric lavage are no longer recommended for routine use at home or in health care facilities (4)[C].

Medication

First Line

• Acetylcysteine (NAC, Mucomyst) should be initiated within 8 hours of ingestion whenever possible; single dose activated charcoal may be given 1 hour after oral NAC. NEVER delay oral NAC for activated charcoal.
• Acetylcysteine may be given p.o. or IV, depending on situation and availability: IV is often preferred, particularly if activated charcoal is given:
  • Currently, IV is the recommended form of administration:
    • Oral loading dose of 140 mg/kg, followed by 70 mg/kg q4h for 17 additional doses. IV loading dose of Acetadote 150 mg/kg over 15 to 60 minutes followed by an infusion of 50 mg/kg over 4 hours (12.5 mg/kg/hour); this is followed by an infusion of 100 mg/kg over the next 16 hours (6.25 mg/kg/hour).
• Contraindications: Medication allergies
• Precautions:
  • Oral NAC may cause significant nausea and vomiting due to its sulfur content; consider IV administration or 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 reactions, including rash, bronchospasm, pruritus, angioedema, tachycardia, or hypotension (higher rates seen in asthmatics and those with atopic history) (5,6)[C].
• 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 oral NAC may adsorb the NAC, limiting its effectiveness.
• Activated charcoal: 1 g/kg p.o. for initial dose; preferably not within 1 hour of NAC administration. Additional concurrent use during NAC therapy is controversial.

Second Line

Oral racemethionine (methionine)

Additional Treatment

Issues for Referral

• Psychiatric and psychological evaluation in emergency room and close follow-up for all after intentional ingestions
• Consider child abuse reporting if neglect led to overdose.

In-Patient Considerations

Initial Stabilization

Aggressive age- and weight-appropriate IV hydration

Admission Criteria

• Toxic and intentional ingestions
• Any reported ingestion with increased LFTs, acidosis on arterial blood gas (ABG), elevated creatinine, etc.

Ongoing Care

Follow-Up Recommendations

• All patients should be evaluated at a health care facility.
• Patients with evidence of organ failure, increased LFTs, or coagulopathy should be evaluated for transfer to a site capable of liver transplant.
• Outpatient for nontoxic accidental ingestions
• Activity may be restricted if significant hepatic damage.

Patient Monitoring

Inquire as to possible ingestion by others (i.e., suicide pacts).

Diet

No special diet, except with severe hepatic damage

Patient Education

• Patients should be counseled to avoid Tylenol if already using combination product containing acetaminophen.
• Education of parents/caregivers during well-child visits
• Anticipatory guidance for caregivers, family, and cohabitants of potentially suicidal patients
• Patient brochure (item no. 1515), Child safety: keeping your home safe for your baby. American Academy of Family Physicians: www.familydoctor.org or http://familydoctor.org/online/famdocen/home/healthy/safety/kids-family/027.html
• Education of patients taking long-term acetaminophen therapy

Prognosis

• Complete recovery with early therapy
• <1% of adult patients develop hepatic failure. King criteria (pH <7.3, PT >100 s [INR >65], creatinine >3.4 mg/dL [>300 µmol/L]) are associated with a poor prognosis and possible need for liver transplant (7)[C].
• Hepatic failure is very rare in children <6 years of age.