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Intravenous N-acetylcysteine May Be Preferred Over Oral for Acetaminophen Overdosere

Question

  • A 15-month old male is transferred to our hospital after accidental overdose of acetaminophen.  He is responsive to pain.  Unsuccessful attempts to administer oral N-acetylcysteine had been made at the outside hospital.  Consideration is given to intravenous N-acetylcysteine as alternative therapy.

Clinical Bottom Lines

  1. Consideration of 52 hours of intravenous N-acetylcysteine (loading dose 140mg/kg, followed by 12 maintenance doses of 70mg/kg every 4 hours) is equivalent to 72 hours of oral N-acetylcysteine (loading dose 140mg/kg, followed by 17 maintenance doses of 70mg/kg every 4 hours) as an antidote for acetaminophen overdose can be made.


Summary of Key Evidence

  1. Open-label clinical trial over a 7-10-year study period.  Decision about route of therapy was made at discretion of treating physician.  Unsuccessful attempt to administer oral N-acetylcysteine (O-NAC) did not exclude a patient from being treated with IV N-acetylcysteine (IV-NAC).1
  2. Patients were eligible for study:  a) Presentation no later than 24 hours after an acute, single overdose of acetaminiphen; b) a plasma concentration placing him or her in at least the "possible" hepatotoxicity risk group.  Ultimate comparisons were made only for patients in the "probable" high risk hepatotoxicity groups because there were no patients in the IV-NAC group with acetaminophen level placing them in the "possible" hepatotoxicity risk group.
  3. Patients were assigned to risk category of "probable" or "high" based upon plasma acetaminophen level/Rumack Nomogram.
  4. Monitoring for both groups included measurement of AST/ALT at time of enrollment and 24 hours thereafter.  Total bili/PT and/or more frequent transaminase measurements were made at discretion of the physician.
  5. Major outcome measures were hepatotoxicity, encephalopathy, need for FFP, and adverse drug reactions.
  6. 25 patients were treated with IV-NAC; 29 patients were counted as historical control subjects and treated with conventional O-NAC. 
  7. The incidence of hepatotoxocity was a function of treatment delay.  Mean treatment delay was 14.4 hours for IV-NAC vs. 10.4 hours in O-NAC.  No events of hepatotoxicity were measured in patients treated within 10 hours of overdose.  Hepatotoxocity occurred in 9.8% of patients treated within 10-24 hours after overdose.  Hepatic encephalopathy occurred in one patient in O-NAC group.  No patients required FFP.  Adverse drug reactions occurred in 2 patients in IV-NAC group and 2 patients in O-NAC group.

Additional Comments

  • The efficacy of N-acetylcysteine as a specific antidote for acetaminophen poisoning depends on its ability to stimulate glutathione synthesis.2,3  Increasing evidence has shown the action of N-acetylcysteine to be dey in microcirculatory blood flow and tissue oxygenation via enhanced oxygen delivery/consumption.4 No randomized controlled trials comparing IV-NAC to O-NAC in children/adults have been published.

  • Oral N-acetylcysteine is the only FDA approved antidote for acetaminophen overdose in the United States.  All usage of IV-NAC at present is investigational.3

  • IV-NAC is treatment of choice for acetaminophen poisoning in Europe.  The theoretic superiority of IV-NAC centers around fact that the most severely poisoned patients develop early nausea and vomiting, making oral treatment impractical.1,3

  • Adverse reaction to IV-NAC include local/diffuse erythema (usually associated with loading dose), fever, dystonic reaction, and anaphylaxis.1

Citation

 

  1. Perry HE, Shannon MW. Efficacy of oral verses intravenous N-acetylcysteine in acetaminophen overdose:  Results of an open-label, clinical trial.  The Journal of Pediatrics 1998; 132:149-152.
  2. Miller RP, Roberts FJ, Tischer LJ. Acetaminophen Elimination Kinetics in Neonates, Children, and Adults.  Clinical Pharmacology and Therapeutics 1976; 19:284-294.
  3. Smilkstein MJ, Bronstein AC, Linden C, et al. Acetaminophen Overdose:  A 48-hour Intravenous N-acetylcyteine treatment protocol.  Annals of Emergency Medicine 1991; 20:1058-1063.
  4. Harrison P, Wendon J, Gimson O, et al.  Improvement By Acetylcysteine of Hemodynamics and Oxygen Transport In Fulminant Hepatic Failure. New England Journal of Medicine 1991; 324:1852-1857.

CAT Author: Naomi Duke,MD

CAT Appraisers: <Reviewers>, MD

Date appraised: August 17, 1998

Last updatedLast updated January 30, 2003
Department of Pediatrics and Communicable Diseases
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