Skip to main content
SpringerLink
Log in

Adducts Post Acetaminophen Overdose Treated with a 12-Hour vs 20-Hour Acetylcysteine Infusion

  • Original Article
  • Published:
Journal of Medical Toxicology Aims and scope Submit manuscript

Abstract

Introduction

Acetaminophen protein adducts in the circulation are a specific biomarker of acetaminophen oxidation, and may be a more sensitive measure of impending hepatic injury following overdose than alanine transaminase (ALT). We performed an exploratory analytical substudy of adducts during a clinical trial (NACSTOP) of abbreviated (12-hour) versus control (20-hour) acetylcysteine to identify any signal of diminished antidotal effectiveness with shortened therapy.

Methods

We measured adducts at 0, 12, and 20 hours from a convenience sample of subjects enrolled in the cluster-controlled NACSTOP trial evaluating a 12-hour (“abbreviated”; 200 mg/kg over 4 hours, 50 mg/kg over 8 hours) vs 20-hour acetylcysteine regimen (“control”; 200 mg/kg over 4 hours, 100 mg/kg over 16 hours). Adducts were assayed using high-performance liquid chromatography/mass spectrometry.

Results

Median ALT 20 hours after the initiation of acetylcysteine was 12 U/L (IQR 8,14) in the abbreviated 12-hour regimen group (N = 8), compared with the control group 16 U/L (IQR 11,21; N = 21) (p = 0.46). Adduct concentrations were similarly low in both groups: abbreviated [(0.005 μmol/L, IQR (0,0.14)] and control [(0.005 μmol/L, IQR (0,0.05)] (p = 0.61).

Conclusions

There were minimal to no acetaminophen protein adducts detected. These findings further support discontinuing acetylcysteine when acetaminophen concentrations are low and liver function tests normal after 12 hours of treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Wong A, McNulty R, Taylor D, Sivilotti M, Greene S, Gunja N, et al. The NACSTOP trial: a multicenter, cluster-controlled trial of early cessation of acetylcysteine in acetaminophen overdose. Hepatology. 2019;69(2):774–84.

    Article  CAS  Google Scholar 

  2. Pettie J, Caparrotta TM, Hunter RW, et al. Safety and efficacy of the SNAP 12-hour acetylcysteine regimen for the treatment of paracetamol overdose. EClinicalMed. 2019.

  3. Johnson MT, McCammon CA, Mullins ME, Halcomb SE. Evaluation of a simplified N-acetylcysteine dosing regimen for the treatment of acetaminophen toxicity. Ann Pharmacother. 2011;45(6):713–20.

    Article  CAS  Google Scholar 

  4. Chiew AL, Isbister GK, Kirby KA, Page CB, Chan BSH, Buckley NA. Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2). Clin Toxicol. 2017;55(10):1055–65.

    Article  CAS  Google Scholar 

  5. Dart RC, Rumack BH. Patient-tailored acetylcysteine administration. Ann Emerg Med. 2007;50(3):280–1.

    Article  Google Scholar 

  6. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol. 2002;40(1):3–20.

    Article  CAS  Google Scholar 

  7. Sivilotti ML, Yarema MC, Juurlink DN, Good AM, Johnson DW. A risk quantification instrument for acute acetaminophen overdose patients treated with N-acetylcysteine. Ann Emerg Med. 2005;46(3):263–71.

    Article  Google Scholar 

  8. Mitchell JR, Jollow DJ, Potter WZ. Acetaminophen induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther. 1973;187(1):185–94.

    CAS  Google Scholar 

  9. Davern ITJ, James LP, Hinson JA, Polson J, Larson AM, Fontana RJ, et al. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology. 2006;130(3):687–94.

    Article  CAS  Google Scholar 

  10. Heard K, Green JL, Anderson V, Bucher-Bartelson B, Dart RC. Paracetamol (acetaminophen) protein adduct concentrations during therapeutic dosing. Br J Clin Pharmacol. 2016;81(3):562–8.

    Article  CAS  Google Scholar 

  11. Wong A, Graudins A. Simplification of the standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning results in a lower incidence of adverse drug reactions. Clin Toxicol. 2016;54(2):115–9.

    Article  CAS  Google Scholar 

  12. McNulty R, Lim JME, Chandru P, Gunja N. Fewer adverse effects with a modified two-bag acetylcysteine protocol in paracetamol overdose. Clin Toxicol. 2018;56(7):618–21.

    Article  CAS  Google Scholar 

  13. Schmidt LE, Rasmussen DN, Petersen TS, Macias-Perez IM, Pavliv L, Kaelin B, et al. Fewer adverse effects associated with a modified two-bag intravenous acetylcysteine protocol compared to traditional three-bag regimen in paracetamol overdose. Clin Toxicol. 2018:1–7.

  14. Wong A, Gunja N, McNulty R, Graudins A. Analysis of an 8-hour acetylcysteine infusion protocol for repeated supratherapeutic ingestion (RSTI) of paracetamol. Clin Toxicol. 2018;56(3):199–203.

    Article  CAS  Google Scholar 

  15. Chiew A, Fountain JS, Graudins A, Isbister GK, Reith D, Buckley NA. Summary statement: new guidelines for the management of paracetamol poisoning in Australia and New Zealand. Med J Aust. 2015;203(5):215–8.

    Article  Google Scholar 

  16. Cook SF, King AD, Chang Y, Murray GJ, Norris HR, Dart RC, et al. Quantification of a biomarker of acetaminophen protein adducts in human serum by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: clinical and animal model applications. J Chromatogr B Analyt Technol Biomed Life Sci. 2015;985:131–41. https://doi.org/10.1016/j.jchromb.2015.01.028.

    Article  CAS  PubMed  Google Scholar 

  17. Curry SC, Padilla-Jones A, Ruha AM, O'Connor AD, Kang AM, Wilkins DG, et al. The relationship between circulating acetaminophen-protein adduct concentrations and alanine aminotransferase activities in patients with and without acetaminophen overdose and toxicity. J Med Toxicol. 2019.

  18. James LP, Chiew A, Abdel-Rahman SM, Letzig L, Graudins A, Day P, et al. Acetaminophen protein adduct formation following low-dose acetaminophen exposure: comparison of immediate-release vs extended-release formulations. Eur J Clin Pharmacol. 2013;69(4):851–7.

    Article  Google Scholar 

  19. Court MH, Zhu Z, Masse G, Duan SX, James LP, Harmatz JS, et al. Race, gender, and genetic polymorphism contribute to variability in acetaminophen pharmacokinetics, metabolism, and protein-adduct concentrations in healthy African-American and European-American volunteers. J Pharmacol Exp Ther. 2017;362(3):431–40.

    Article  CAS  Google Scholar 

  20. Heard KJ, Green JL, James LP, Judge BS, Zolot L, Rhyee S, et al. Acetaminophen-cysteine adducts during therapeutic dosing and following overdose. BMC Gastroenterol. 2011;11:20.

    Article  CAS  Google Scholar 

  21. Prescott LF. Paracetamol: past, present, and future. Am J Ther. 2000;7(2):143–7.

    Article  CAS  Google Scholar 

  22. Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. Br J Clin Pharmacol. 1980;10(Suppl 2):291S–8S.

    Article  Google Scholar 

  23. Wong A, Homer N, Dear JW, Choy KW, Doery J, Graudins A. Paracetamol metabolite concentrations following low risk overdose treated with an abbreviated 12-h versus 20-h acetylcysteine infusion. Clin Toxicol. 2019;57(5):312–7.

    Article  CAS  Google Scholar 

  24. Kietzmann T. Metabolic zonation of the liver: the oxygen gradient revisited. Redox Biol. 2017;11:622–30.

    Article  CAS  Google Scholar 

  25. Wong A, Nejad C, Gantier M, Choy KW, Doery J, Graudins A. MicroRNA from a 12-h versus 20-h acetylcysteine infusion for paracetamol overdose. Hum Exp Toxicol. 2019;38(6):646–54.

    Article  CAS  Google Scholar 

  26. Wong A, Graudins A. Risk prediction of hepatotoxicity in paracetamol poisoning. Clin Toxicol. 2017;55(8):879–92.

    Article  CAS  Google Scholar 

  27. Heard K, Green JL, Anderson V, Bucher-Bartelson B, Dart RC. A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration. BMC Pharmacol Toxicol. 2014;15:39.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Clinical Sciences, Department of Medicine, Monash University, Melbourne, Victoria, Australia

    Anselm Wong & Andis Graudins

  2. Centre for Integrated Critical Care, University of Melbourne, Melbourne, Victoria, Australia

    Anselm Wong

  3. Victorian Poisons Information Centre and Austin Toxicology Service, Austin Hospital, Heidelberg, Victoria, 3084, Australia

    Anselm Wong

  4. Rocky Mountain Poison and Drug Center, Denver Health and Hospitals, Denver, CO, USA

    Kennon Heard

  5. Section of Medical Pharmacology and Toxicology, Department of Emergency Medicine, University of Colorado, Aurora, CO, USA

    Kennon Heard

  6. Monash Toxicology Service, Monash Health, School of Clinical Sciences, Department of Medicine, Monash University, Melbourne, Victoria, Australia

    Andis Graudins

  7. Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, CO, USA

    Richard Dart

  8. Departments of Emergency Medicine, and of Biomedical & Molecular Sciences, Queen’s University, Kingston, Ontario, Canada

    Marco L. A. Sivilotti

Authors
  1. Anselm Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kennon Heard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andis Graudins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard Dart
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marco L. A. Sivilotti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anselm Wong.

Ethics declarations

Fully informed consent from participants was obtained to participate in the study. Ethics approval was obtained from the Monash Health Ethics Research Committee.

Conflicts of Interest

None.

Additional information

Supervising Editor: Michael Levine, MD

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wong, A., Heard, K., Graudins, A. et al. Adducts Post Acetaminophen Overdose Treated with a 12-Hour vs 20-Hour Acetylcysteine Infusion. J. Med. Toxicol. 16, 188–194 (2020). https://doi.org/10.1007/s13181-020-00757-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13181-020-00757-9

Keywords

Search

Navigation