Acetaminophen Poisoning

BASICS

Description

Disorder characterized by hepatic necrosis following large acetaminophen ingestions.
Clinical manifestations vary with time since ingestion, classified into four stages.
Toxicity usually from single large ingestion but can occur with smaller doses in chronic alcohol use, malnutrition, or medications affecting hepatic metabolism.
Toxic dose: >12 g in adults or >250 mg/kg in children.

Epidemiology

Two-thirds of hospitalizations from acetaminophen toxicity are intentional ingestions.
80% adults; 70% women.
50% of poison control calls involve unintentional pediatric ingestions (<5 years).
Second leading cause of liver transplantation worldwide.
50,000 ED visits, >2,500 hospitalizations, ~500 deaths annually in the US.

ETIOLOGY AND PATHOPHYSIOLOGY

Pharmacokinetics

Fully absorbed in duodenum; peak serum levels 10-20 µg/mL by 2 hours (may be delayed in toxicity).
Adult therapeutic dose: 325-1000 mg every 4-6 hours; max 4 g/day.
Pediatric dose: 10-15 mg/kg every 4-6 hours; max 5 doses/24 hrs or 75 mg/kg/day.
Elimination half-life: 2-4 hours; delayed with extended-release forms.

Pathophysiology

Liver metabolizes ~96% of acetaminophen; 2-4% excreted unchanged.
Therapeutic doses produce mostly benign metabolites; 5-10% converted to toxic NAPQI.
NAPQI detoxified by glutathione conjugation.
Toxic ingestions saturate glucuronidation/sulfation → glutathione depletion → NAPQI accumulation → hepatocellular damage.

RISK FACTORS

Co-ingestion of other substances.
Psychiatric illness or suicide attempt history.
Chronic alcohol use.
Malnutrition.
Prior weight loss surgery.

GENERAL PREVENTION

Poison Control Center: 800-222-1222 (US).
FDA labeling guidance: FDA Guidance.

Geriatric Considerations

Increased risk of hepatic damage.
Limit acetaminophen to ≤3,000 mg/day in elderly and patients with liver disease/alcohol use.

Pediatric Considerations

Children may be less susceptible due to higher glutathione stores.

Pregnancy Considerations

Increased risk of spontaneous abortion with overdose, especially early gestation.
Delayed NAC treatment increases fetal risk.
IV NAC preferred in pregnancy due to better bioavailability.

DIAGNOSIS

Clinical Presentation by Stage

Stage 1 (0-24 hours): often asymptomatic first 8 hrs; nausea, vomiting, anorexia, diaphoresis; labs usually normal.
Stage 2 (24-72 hours): decreased nausea, RUQ pain, hepatomegaly; elevated aminotransferases.
Stage 3 (72-96 hours): recurrent nausea, vomiting, malaise; jaundice, confusion, coma; peak liver enzymes; prolonged PT/INR; multi-organ failure common.
Stage 4 (5+ days): recovery phase; lab normalization; typically full recovery without sequelae.
Fulminant hepatic failure rare (<1% adults, very rare in children <6).

History

Focus on ingestion type (immediate vs extended release, coingestants), amount, timing, intent.
Ask about alcohol use, hepatitis, prior surgeries.

Physical Exam

Vitals, general appearance (somnolence, fatigue, pallor, dehydration).
Hepatomegaly, RUQ tenderness.

Differential Diagnosis

Co-ingestants (alcohol, opiates, aspirin).
Other hepatotoxins: Amanita phalloides, yellow phosphorus, carbon tetrachloride.
Other hepatitis causes: alcoholic, viral, ischemic.

DIAGNOSTIC TESTS & INTERPRETATION

Labs

Plasma acetaminophen level ≥4 hrs post-ingestion; repeat at 6 & 8 hrs if extended-release ingested.
Treat if levels above toxicity line.
Liver function tests: ALT, AST, bilirubin, PT/INR, LDH.
Additional: electrolytes, glucose, BUN, creatinine, urinalysis, UDS, serum alcohol, salicylate.
Pregnancy test for females.
ABG if acidosis suspected.
Imaging (US/CT) only if acute liver/kidney injury present to rule out other causes.

Interpretation

PT/INR and LFTs rise in stage 2-3.
ALT improvement indicates recovery.

TREATMENT

Contact Poison Control (800-222-1222).
N-Acetylcysteine (NAC): replenishes glutathione, reduces mortality (from 5% to 0.7%).
Rumack-Matthew nomogram: guides treatment based on acetaminophen plasma level at ≥4 hours post ingestion.
NAC indicated if plasma level at or above “treatment line” (150 µg/mL at 4h, 75 µg/mL at 8h, 37 µg/mL at 12h).
Start NAC ideally within 8 hours.
Activated charcoal (1 g/kg PO) if within 1-4 hours of ingestion; do not delay NAC for charcoal.
Ipecac and gastric lavage no longer recommended.

Medication Regimens

First Line

Empiric NAC within 8 hours, effective up to ≥36 hours post ingestion.
IV NAC (preferred for shorter hospitalization):
Two-bag regimen: 200 mg/kg IV over 4 hrs + 100 mg/kg IV over 16 hrs (total 300 mg/kg over 20 hrs).
Oral NAC:
Loading dose 140 mg/kg, then 70 mg/kg q4h × 17 doses (72-hour regimen).
NAC Adverse Effects:
Oral: nausea, vomiting (may need NG tube).
IV: anaphylactoid reactions (3-6%), treat by slowing infusion, antihistamines.
Antiemetics (metoclopramide, ondansetron) for nausea.
NAC failure rare (3-7%).

Second Line

Hemodialysis for massive ingestions (>1000 mg/L), severe acidosis, coma, hypotension, or renal failure.

ISSUES FOR REFERRAL

Behavioral health for intentional ingestions.
Child abuse reporting if applicable.

ADMISSION AND NURSING

Hospitalize if unstable vitals or abnormal labs.
Psychiatric transfer when medically stable.
IV fluids for hydration.

ONGOING CARE

Follow-Up

Evaluate for organ failure, coagulopathy, transplant need.
Restrict activity if liver damage significant.
Outpatient care for nontoxic accidental ingestions.

Diet

No special diet unless severe hepatic damage.

PATIENT EDUCATION

Avoid acetaminophen and combination products if possible.
Educate caregivers on OTC dosing, storage.
Guidance for suicidal patients’ families.
Counsel on risks of long-term acetaminophen therapy.

PROGNOSIS

Early therapy leads to complete recovery, especially in stage 4.
10% with severe complications develop necrosis, encephalopathy, or need transplant.
Hepatic failure rare in children <6.

COMPLICATIONS

Recovery typically complete with rare sequelae.

REFERENCES

Chiew AL, Gluud C, Brok J, et al. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2018;(2):CD003328.
Dart RC, Mullins ME, Matoushek T, et al. Management of acetaminophen poisoning in the US and Canada: consensus statement. JAMA Netw Open. 2023;6(8):e2327739.

Codes

Code	Description
T39.1X4A	Poisoning by 4-Aminophenol derivatives, undetermined, initial encounter
K71.10	Toxic liver disease with hepatic necrosis, without coma
T39.1X1A	Poisoning by 4-Aminophenol derivatives, accidental, initial encounter

Clinical Pearls

Immediately notify Poison Control for management (800-222-1222 US).
Treat when acetaminophen levels ≥ treatment line on Rumack-Matthew nomogram.
Start NAC within 8 hours for optimal hepatic protection.
Empirically treat near 8 hours while awaiting labs.
Two-bag IV NAC over 20 hours preferred regimen.
Oral NAC should be diluted and served with a lid and straw.
For extended-release ingestion, monitor plasma levels at 4, 6, and 8 hours; treat if any elevated.