Lit of the Week — Acute Acetaminophen Toxicity and NAC

Lit of the Week – 3/29/16

RMN

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 1st 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

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