Lit of the Week — Acute Acetaminophen Toxicity and NAC

Lit of the Week – 3/29/16

Rumack BH, Peterson RC, Koch GG, Amara IA. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981 Feb 23;141(3 Spec No):380-5. PubMed PMID: 7469629.

http://www.ncbi.nlm.nih.gov/pubmed/7469629

Clinical question / background:

• Does N-acetylcysteine prevent or moderate hepatotoxicity secondary to acute acetaminophen overdose?

Design:

• Nationwide, multiclinic open study
• Started in 1976 at the Rocky Mountain Poison Center, Denver
• 662 consecutive patients with acetaminophen overdose

• Inclusion: Age > 12 y/o, history of known or suspected acute ingestion of 7.5 g or more of acetaminophen within 24 hours of presentation, plasmal acetaminophen level in toxic range on the nomogram
• Exclusion: ingestion > 24h old

• Primary outcome: incidence of hypotoxicity secondary to acute acetaminophen ingestion
  • Clinically significant hepatotoxicity defined as AST > 1000 IU/L
  • Patients grouped based on time of ingestion to administration of NAC
    • < 10 hours
    • 10-16 hours
    • 16-24 hours
  • Secondary outcomes: mortality, safety of oral NAC

Intervention:

• NAC loading dose: 140 mg/kg PO x 1
• NAC maintenance dose: 70 mg/kg PO q4 for 17 additional doses
• Supportive measures, gastric lavage up front

Control:

• None

Results:

• Incidence of hepatotoxicity and time to treatment for patients with acetaminophen concentration in probable toxic range (line intersecting 200 mg/mL (1324 mmol/L) at 4 hours and 50 mg/mL (331 mmol/L) at 12 hours) were:
  • 7% when treated within 10 hours of ingestion
  • 29% when treated within 10 to 16 hours of ingestion
  • 62% when treated within 16 to 24 hours of ingestion
• Statistically significant trend in reduction severity of toxicity with earlier onset of NAC treatment
• Alcohol congest as possible protective effect

Take-home:

• NAC is a safe and effective management option of acetaminophen overdose and its effects are more beneficial with early administration < 10 hours after overdose ingestion

Strengths:

• Large study
• Simple protocol with reproducible results in subsequent studies
• Mainstay of treatment for acetaminophen overdose remains NAC

Weaknesses / Critiques

• No control
• Unable to ascertain effects on chronic ingestion
• PO administration only

Follow-up / Real World Application

• Acute Acetaminophen Ingestion – remember that Rumack-Mathew Nomogram ONLY for acute ingestions
• VERY IMPORTANT to ascertain INGESTION TIME – use EARLIEST if patient took multiple ingestions over a period of hours
• Call Poison control center à 5-9000, ext 2; (404-616-9000 ext. 2)
  • Ingestion < 4 hours
    • AC if < 3 hours post-ingestion
    • Send 4-hour APAP level and treat if necessary
  • Ingestion 4-24 hours
    • If APAP level available by 8 hours post-ingestion, can wait before starting NAC
    • If APAP level will be available > 8 hour post-ingestion or patient presenting > 8hours post ingestion, START NAC and send APAP level to guide treatment
  • Ingestion > 24 hours or unknown ingestion time
    • Send APAP level, LFTs, Coags, ABG
    • Give 1^st dose of NAC
    • If APAP level > 10, or elevated LFTs à continue NAC
      • pH <7.3, PT > 100, Cr >3.3 or AMS, consider transplant eval
    • If APAP level normal and LFTs wnl, stop NAC
  • NAC Dosing
    • PO – 72 hr protocol
      • 140 mg/kg PO load
      • 70 mg/kg PO q4hr x 17 additional doses
    • IV – 21 hr protocol
      • Load: 150 mg/kg in 100 mL D5W over 60 min
      • Maintenance: 50 mg/gk in 250 mL D5W over 4 hrs
      • Third dose: 100 mg/kg in 500 mL D5W over 16 hrs