Acetylcysteine

- 600mg effervescent tablets and oral capsules (PO)

- 6gr/60ml (100mg/ml) solution vial (PO)

- 6gr/30ml (200mg/ml) injection vial (IV)

Emergency Medicine Executive Summary

(Summary version, Updated November 2021)

N-Acetylcisteine (NAC) is a mucolytic, antioxidant and a glutathione-inducer. It is positioned as the cornerstone antidote for the prevention and treatment of liver toxicity secondary to acetaminophen (APAP) overdose (6, 10, 11, 12, 15, 16), with US-FDA approval for IV, PO and effervescent tablets (9, 13, 14).

  • Adult and Pediatric dose for acetaminophen overdose: oral administration, 18 doses total.

  • Loading dose: 140mg/kg PO.

  • Dose 2 to 17: repeated doses every 4 hours of 70mg/kg PO.

Why use NAC:

It has several roles in preventing injury and diminishing ongoing hepatic damage due acetaminophen overdose (1, 3, 5, 6, 11, 15):

  1. Increases sulfation of APAP before it is metabolized to NAPQI.

  2. Detoxifies NAPQI as a glutathione substitute.

  3. Increases available glutathione as a substrate for its synthesis.

  4. Decreases cellular damage secondary to NAPQI toxicity through nonspecific mechanisms (free radical scavenging, enhanced oxygen delivery, increased mitochondrial ATP production, and antioxidant effects).

Election of PO versus IV formulation depends mostly on availability, as they are equally efficacious if successfully administered within 8 hours (the most significant efficacy predictor; with the greatest outcomes achieved when administered within 6-8 hours of APAP ingestion when glutathione stores are depleted around 30% of normal levels)(5, 7, 8, 15).

IV NAC might be preferred in patients who: (i) are seriously poisoned, (ii) presented late at the ED, (iii) are thought to be particularly susceptible to APAP hepatotoxicity, (iv) present nausea and vomiting, and (v) who are unable to take NAC orally. (5). IV formulation carries a significant incidence of mild anaphylactoid reactions, ranging 3.5 to 50% in published series, mostly occurring within the first hour (5), but few events of nausea and vomiting (3%) compared with PO administration (20%)(15).

PO NAC administration on the other hand, besides nausea and vomiting (20%), other mild or serious adverse effects are quite rare. This is a reason why it should be considered in mild and moderate cases of APAP overdose in stable patients without any other immediate risk situations (5).

When to start NAC therapy

In all patients with hepatotoxicity risk secondary to APAP overdose, including the following scenarios:

  1. In acute overdose, plot a single APAP level on the Modified Rumack-Matthew normogram using the earliest possible time of ingestion. Initiate NAC if the plot is over the treatment line.

  2. In a suspected acute single ingestion of ≥150mg/kg and:

      1. APAP levels are unavailable or,

      2. There is a delay of>8 hours from time of ingestion and obtaining results

  3. If there are signs of hepatotoxicity (primarily GOT elevation) due to a supratherapeutic APAP dose

  4. Unknown ingestion time and APAP levels >10mcg/ml

Adult and Pediatric dose (PO, oral)

Acetaminophen overdose, prevention and treatment of hepatic toxicity:

Calculate dose with actual body weight.

  • Oral (solution and effervescent tablets): 18 doses total*

  • Loading dose: 140mg/kg PO.

  • Dose 2 to 17: repeated doses every 4 hours of 70mg/kg PO.

*If the patient vomits within the 1st hour of any dose, repeat that dose.

Adult and Pediatric dose (IV, intravenous)

Acetaminophen overdose, prevention and treatment of hepatic toxicity:
Calculate dose with actual body weight.

  • Intravenous (three-bag regimen):

Patients ≥41 kg:

  • Loading dose:
    150mg/kg in 200ml of diluent in 60min.

  • Dose 2:
    50mg/kg in 500ml of diluent in 4h.

  • Dose 3:
    100mg/kg in 1000ml of diluent in 16h.

Patients 21 - 40 kg

  • Loading dose:
    150mg/kg in 100ml of diluent in 60min.

  • Dose 2:
    50mg/kg in 250ml of diluent in 4h.

  • Dose 3:
    100mg/kg in 500ml of diluent in 16h.

Patients 5-20 kg:

  • Loading dose:
    150mg/kg in 3 ml/kg of diluent in 60min.

    • Dose 2:
      50mg/kg in 7 ml/kg of diluent in 4h.

    • Dose 3:
      100mg/kg in 14 ml/kg of diluent in 16h.

*Diluent solutions for IV NAC: 0.45% NaCl, or 5% dextrose.

References

  1. Mitchell JR, Thorgeirsson SS, Potter WZ, Jollow DJ, Keiser H. Acetaminophen-induced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther. 1974;16(4):676-684. doi:10.1002/cpt1974164676.
    Pubmed

  2. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55(6):871-876.
    Pubmed

  3. Harrison PM, Keays R, Bray GP, Alexander GJ, Williams R. Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Lancet. 1990.
    Pubmed

  4. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol. 2002.
    Pubmed

  5. Prescott L. Oral or intravenous N-acetylcysteine for acetaminophen poisoning? Ann Emerg Med. 2005.
    Pubmed

  6. Wolf SJ, Heard K, Sloan EP, Jagoda AS; American College of Emergency Physicians. Clinical policy: critical issues in the management of patients presenting to the emergency department with acetaminophen overdose. Ann Emerg Med. 2007.
    Pubmed

  7. Green JL, Heard KJ, Reynolds KM, Albert D. Oral and Intravenous Acetylcysteine for Treatment of Acetaminophen Toxicity: A Systematic Review and Meta-analysis. West J Emerg Med. 2013.
    Pubmed

  8. Schwarz E, Cohn B. Is intravenous acetylcysteine more effective than oral administration for the prevention of hepatotoxicity in acetaminophen overdose?. Ann Emerg Med. 2014.
    Pubmed

  9. US-FDA (US Food and Drug Administration), Drug Approval Package: Cetylev effervescent tablets for oral solution, 500 mg and 2.5 grams (acetylcysteine). Approval date January 2016.
    US-FDA

  10. Flamm SL, Yang YX, Singh S, Falck-Ytter YT; AGA Institute Clinical Guidelines Committee. American Gastroenterological Association Institute Guidelines for the Diagnosis and Management of Acute Liver Failure. Gastroenterology. 2017.
    Pubmed

  11. Walls RM, Hockberger RS, Gausche-Hill M. Rosen’s Emergency Medicine : Concepts and Clinical Practice. 9th edition. Philadelphia, PA: Elsevier; 2018.
    Elsevier

  12. Chiew AL, Gluud C, Brok J, Buckley NA. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2018.
    Pubmed

  13. NIH-NLM (National Institues of Health National Library of Medicine). DailyMed. Label: Acetylcysteine solution. Updated in July 2019.
    Dailymed

  14. NIH-NLM (National Institues of Health National Library of Medicine). DailyMed. Label: Acetadote - acetylcysteine injection, solution. Updated in October 2019.
    Dailymed

  15. Nelson LS, Howland MA, Lewin NA. Goldfrank’s Toxicologic Emergencies. 11th ed. New York, NY: McGraw-Hill Education; 2019.
    McGraw-Hill

  16. Chiew AL, Reith D, Pomerleau A, et al. Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand. Med J Aust. 2020.
    Pubmed

Resources:
Modified Rumack-Matthew Normogram

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