Description

• Acetaminophen (APAP) is available alone, in combination with oral opiate, and in >200 OTC cold remedies:
  • One of the most common drugs implicated in intentional and unintentional poisonings
  • One of the most common reasons for hepatic transplantation in the U.S.
• N-acetyl-p-benzoquinone imine (NAPQI) produced when APAP metabolized by cytochrome P-450:
  • NAPQI normally detoxified by glutathione
  • In overdose, glutathione is quickly depleted and NAPQI causes hepatic damage
  • N-acetylcysteine (NAC) replenishes the liver's glutathione stores
    
    
    
    Rumack–Matthew nomogram.
    (Adapted from Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871–876.)
• Increased risk of toxicity:
  • Patients with poor nutrition have decreased glutathione stores
• Pharmacokinetics:
  • APAP half-life:
    • 2.5–4 hr in a nonoverdose setting
    • >4 hr in overdose
• Toxic dose >150 mg/kg acutely
• Probable toxic level is 140 mcg/mL at 4-hr postingestion (see nomogram for acute intoxication)
• Therapeutic plasma concentration is 5–20 mcg/mL

Signs and Symptoms

• Phase 1: 0.5–24-hr postingestion:
  • Nausea, vomiting, malaise
  • Occurs with large overdoses
  • May not be present with smaller toxic doses
• Phase 2: 24–72-hr postingestion:
  • Decreased GI symptoms
  • Hepatic damage is occurring
  • Right upper quadrant pain and tenderness
  • Elevation of liver enzymes, PT/INR, bilirubin
  • Oliguria
  • Prolonged (>4 hr) APAP half-life implies hepatic toxicity
• Phase 3: 72–96-hr postingestion:
  • Critical time period in the prognosis
  • Peak liver function abnormalities
  • Hepatic encephalopathy develops
  • If the PT/INR continues to rise and/or renal insufficiency develops beyond the 3rd d postingestion, there is high likelihood that the patient will require hepatic transplantation
• Phase 4: 96-hr to 10-d postingestion:
  • Resolution of hepatic injury or progression to complete hepatic failure

Essential Workup

• Ingestion history of all APAP-containing products
• Time of ingestion
• APAP level:
  • Obtain 4-hr postingestion level or immediately on presentation if >4-hr postingestion.
  • Use Rumack–Matthew nomogram as therapeutic guide for single acute overdose (see ).
  • In staggered ingestions or very late presenters (>24 hr after acute ingestion), obtain level but do not use nomogram for therapeutic guidance.
• Call poison center ([800] 222-1222) or toxicologist

Diagnostic Tests and Interpretation

• APAP level
• Electrolytes, BUN, creatinine, and glucose
• Liver enzymes:
  • Elevated AST is the first abnormality detected
  • AST/ALT levels may rise >10,000 in stage III of toxicity
  • Bilirubin
• PT/INR
• Pregnancy test
• Toxicology screen

Differential Diagnosis

• Suspect APAP as coingestant with other drugs in overdose
• Causes of acute onset hepatotoxicity:
  • Infectious hepatitis
  • Reye syndrome
  • Amanita sp. mushrooms toxicity
  • Herbal and dietary supplements
  • Alcohol overuse
  • Other drug ingestions

Pre Hospital

• Transport all pill bottles/pills involved in overdose for identification in ED
• OTC cold remedies often contain APAP

Initial Stabilization/Therapy

• Airway, breathing, circulation (ABCs)
• Administer supplemental oxygen
• Administer naloxone, thiamine, D₅₀ (or Accu-Chek) for altered mental status

Ed Treatment/Procedures

• Supportive care:
  • IV fluids
  • Antiemetics
• Gastric decontamination:
  • Administer a single dose of activated charcoal if recent ingestion

• Administer if toxic level detected as defined by Rumack–Matthew nomogram
• NAC virtually 100% hepatoprotective if initiated within 8 hr of an acute overdose
• NAC available in oral form or IV form
• <8-hr postingestion:
  • Check APAP level
  • Initiate NAC if APAP level will not be available within 8 hr of ingestion and toxic ingestion suspected
  • Discontinue NAC if APAP level nontoxic
• ≥8-hr postingestion:
  • Initiate NAC immediately if suspected toxic ingestion
  • Check APAP level
  • Discontinue NAC if APAP level is nontoxic
• >24-hr postingestion or repeated staggered APAP ingestion:
  • Initiate NAC if:
    • Ingestion >150-mg/kg APAP
    • Symptomatic
    • Abnormal hepatic screening panel
    • Discontinue NAC if APAP falls to nondetectable level and LFTs improve by 36-hr postingestion
    • Call poison center ([800] 222-1222) or toxicologist for help

• IV NAC:
  • Acetadote® infusion given per manufacturer's instructions:
    • Given over 21 hr in acute overdose
    • Duration may need to be extended if abnormal LFTs or in late presenters; consult poison center or toxicologist
• Oral NAC:
  • Poor taste and odor:
    • Dilute to 5% with fruit juice or soft drink to increase palatability
  • Use antiemetics (metoclopramide or ondansetron) liberally to facilitate PO administration
  • If the patient vomits NAC within 1 hr of administration, repeat the dose
  • Administer NAC as a drip through nasogastric (NG) tube if vomiting continues
  • Given q4h

• No teratogenicity with NAC
• NAC may be effective in protecting fetal liver:
  • Fetal liver metabolizes APAP to toxic NAPQI after 14-wk gestation

Medication

• Acetadote: 21-hr IV infusion: 150 mg/kg over 60 min, then 50 mg/kg over 4 hr, then 100 mg/kg over 16 hr for total dose 300 mg/kg (see package insert for additional guidance, especially for pediatric infusion dosing)
• NAC: 140-mg/kg PO loading (adult and pediatric) followed by 70 mg/kg q4h for 17 additional doses
• Activated charcoal: 1–2 g/kg PO
• Dextrose: D₅₀W 1 amp (50 mL or 25 g; peds: D₂₅W 2–4 mL/kg) IV
• Metoclopramide: Start with 10 mg (peds: 0.1–0.2 mg/kg) IV (0.8 mg/kg/24 hr max.)
• Naloxone (Narcan): 0.4–2 mg (peds: 0.1 mg/kg) IV or IM initial dose
• Ondansetron: >80 kg, 12 mg; 45–80 kg, 8 mg (peds: 0.15 mg/kg) IV
• Thiamine (vitamin B₁): 100 mg (peds: 50 mg) IV or IM

Disposition

• Hepatotoxic level of APAP requiring full course of NAC therapy (see Treatment)
• LFT abnormalities in the setting of staggered ingestion or late presentation
• Nontoxic suicide attempt requiring psychiatric treatment

Follow-Up Recommendations

• Substance abuse referral for patients with oral opiate abuse
• Patients with unintentional (accidental) poisoning require poison prevention counseling
• Patients with intentional (e.g., suicide) poisoning require psychiatric evaluation