Annals of Emergency Medicine
Volume 54, Issue 4 , Pages 606-614 , October 2009

Comparison of the 20-Hour Intravenous and 72-Hour Oral Acetylcysteine Protocols for the Treatment of Acute Acetaminophen Poisoning

Presented at the North American Congress of Clinical Toxicology, October 2006, San Francisco, CA, and October 2007, New Orleans, LA; and the Canadian Association of Emergency Physicians, June 2007, Victoria, British Columbia, Canada, and June 2009, Calgary, Alberta, Canada.

  • Mark C. Yarema, MD

      Affiliations

    • Division of Emergency Medicine and Department of Family Medicine, University of Calgary, Calgary, Alberta, Canada
    • Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
    • Corresponding Author InformationAddress for correspondence: Mark Yarema, MD, Department of Emergency Medicine, Foothills Medical Centre, C231, 1403 29th St NW, Calgary, Alberta, Canada T2N 2T9; 403-944-1596, Fax 403-944-2419
  • ,
  • David W. Johnson, MD

      Affiliations

    • Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
    • Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
  • ,
  • Randall J. Berlin, MD

      Affiliations

    • Division of Emergency Medicine and Department of Family Medicine, University of Calgary, Calgary, Alberta, Canada
  • ,
  • Marco L.A. Sivilotti, MD, MSc

      Affiliations

    • Departments of Emergency Medicine and Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada
    • Ontario Regional Poison Information Centre/Centre Anti-Poison de l'Ontario, Toronto, Ontario, Canada
  • ,
  • Alberto Nettel-Aguirre, PhD, PStat

      Affiliations

    • Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
    • Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
  • ,
  • Rollin F. Brant, PhD

      Affiliations

    • Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada
  • ,
  • Daniel A. Spyker, MD, PhD

      Affiliations

    • Department of Biopharmaceutical Sciences, University of California–San Francisco, San Francisco, CA
  • ,
  • Benoit Bailey, MD, MSc

      Affiliations

    • Division of Emergency Medicine, CHU Sainte Justine, Montréal, Quebec, Canada
  • ,
  • Dominic Chalut, MD

      Affiliations

    • Department of Pediatrics, McGill University Health Centre, Montréal, Quebec, Canada
  • ,
  • Jacques S. Lee, MD, MSc

      Affiliations

    • Division of Emergency Medicine, University of Toronto, Toronto, Ontario, Canada
    • Department of Emergency Services, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
  • ,
  • Amy C. Plint, MD, MSc

      Affiliations

    • Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada
    • Department of Emergency Medicine, University of Ottawa, Ottawa, Ontario, Canada
  • ,
  • Roy A. Purssell, MD

      Affiliations

    • Department of Emergency Medicine, University of British Columbia, Vancouver, British Columbia, Canada
    • Drug and Poison Information Centre of British Columbia, Vancouver, British Columbia, Canada
  • ,
  • Tim Rutledge, MD

      Affiliations

    • Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
  • ,
  • Catherine A. Seviour, MD

      Affiliations

    • Department of Medicine (Emergency Medicine), Memorial University of Newfoundland, St. John's, Newfoundland, Canada
  • ,
  • Ian G. Stiell, MD, MSc

      Affiliations

    • Department of Emergency Medicine, University of Ottawa, Ottawa, Ontario, Canada
  • ,
  • Margaret Thompson, MD

      Affiliations

    • Division of Emergency Medicine, University of Toronto, Toronto, Ontario, Canada
    • Ontario Regional Poison Information Centre/Centre Anti-Poison de l'Ontario, Toronto, Ontario, Canada
  • ,
  • Jeffrey Tyberg, MD

      Affiliations

    • Division of Emergency Medicine, University of Toronto, Toronto, Ontario, Canada
    • Department of Emergency Services, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
  • ,
  • Richard C. Dart, MD, PhD

      Affiliations

    • Rocky Mountain Poison and Drug Center, Denver Hospital Health Authority, Denver, CO
  • ,
  • Barry H. Rumack, MD

      Affiliations

    • Department of Pediatrics, University of Colorado School of Medicine, Denver, CO

Received 9 February 2009 ,Revised 7 April 2009 ,Accepted 7 May 2009.

References 

  1. Bronstein AC, Spyker D, Cantilena LR, et al. 2007 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th annual report. Clin Toxicol. 2008;46:927–1057
  2. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42:1364–1372
  3. Smilkstein MJ, Knapp GL, Kulig KW, et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose (Analysis of the National Multicenter Study (1976 to 1985)). N Engl J Med. 1988;319:1557–1562
  4. Prescott LF, Illingworth RN, Critchley JA, et al. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. BMJ. 1979;2:1097–1100
  5. Buckley NA, Whyte IM, O'Connell DL, et al. Oral or intravenous N-acetylcysteine (Which is the treatment of choice for acetaminophen (paracetamol) poisoning?). J Toxicol Clin Toxicol. 1999;37:759–767
  6. Brok J, Buckley N, Gluud C. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2006;(3):CD003328
  7. Culley CM, Krenzelok EP. A clinical and pharmacoeconomic justification for intravenous acetylcysteine: a US perspective. Toxicol Rev. 2005;24:131–143
  8. Smith SW, Howland MA, Hoffman RS, et al. Altered acetaminophen pharmacokinetics and hepatotoxicity associated with premature cessation of intravenous N-acetylcysteine therapy. Ann Pharmacother. 2008;42:1333–1339
  9. Sivilotti ML, Yarema MC, Juurlink DN, et al. A risk quantification instrument for acute acetaminophen overdose patients treated with N-acetylcysteine. Ann Emerg Med. 2005;46:263–271
  10. Rumack BH, Peterson RC, Koch GG, et al. Acetaminophen overdose: 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981;141:380–385
  11. Rumack BH, Peterson RG. Acetaminophen overdose: incidence, diagnosis, and management in 416 patients. Pediatrics. 1978;62:898–903
  12. Peterson RG, Rumack BH. Age as a variable in acetaminophen overdose. Arch Intern Med. 1981;141:390–393
  13. Waring WS, Stephen AF, Malkowska AM, et al. Acute ethanol coingestion confers a lower risk of hepatotoxicity after deliberate acetaminophen overdose. Acad Emerg Med. 2008;15:54–58
  14. Myers RP, Li B, Shaheen AA. Emergency department visits for acetaminophen overdose: a Canadian population-based epidemiologic study (1997-2002). CJEM. 2007;9:267–274
  15. Waring WS, Stephen AF, Robinson OD, et al. Lower incidence of anaphylactoid reactions to N-acetylcysteine in patients with high acetaminophen concentrations after overdose. Clin Toxicol. 2008;46:496–500
  16. Bauer DF. Constructing confidence sets using rank statistics. J Am Stat Assoc. 1972;67:687–690
  17. Nguyen GC, Sam J, Thuluvath PJ. Hepatitis C is a predictor of acute liver injury among hospitalizations for acute acetaminophen overdose in the United States: a nationwide analysis. Hepatology. 2008;48:1336–1341
  18. Gilbert EH, Lowenstein S, Koziol-McLean J, et al. Chart reviews in emergency medicine research: where are the methods?. Ann Emerg Med. 1996;27:305–308
  19. Worster A, Bledsoe RD, Cleve P, et al. Reassessing the methods of medical record review studies in emergency medicine research. Ann Emerg Med. 2005;45:448–451
  20. Prescott L, Roscoe P, Wright N, et al. Plasma paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet. 1971;297:519–522
  21. Kobrinsky NL, Hartfield D, Horner H, et al. Treatment of advanced malignancies with high-dose acetaminophen and N-acetylcysteine rescue. Cancer Invest. 1996;14:202–210
  22. Whyte IM, Francis B, Dawson AH. Safety and efficacy of intravenous N-acetylcysteine for acetaminophen overdose: analysis of the Hunter Area Toxicology Service (HATS) database. Curr Med Res Opin. 2007;23:2359–2368
  23. Prescott LF, Donovan JW, Jarvie DR, et al. The disposition and kinetics of intravenous N-acetylcysteine in patients with paracetamol overdosage. Eur J Clin Pharmacol. 1989;37:501–506
  24. Ekins BR, Ford DC, Thompson MI, et al. The effect of activated charcoal on N-acetylcysteine absorption in normal subjects. Am J Emerg Med. 1987;5:483–487
  25. Chamberlain JM, Gorman RL, Oderda GM, et al. Use of activated charcoal in a simulated poisoning with acetaminophen: a new loading dose for N-acetylcysteine?. Ann Emerg Med. 1993;22:1398–1402
  26. Renzi FP, Donovan JW, Martin TG, et al. Concomitant use of activated charcoal and N-acetylcysteine. Ann Emerg Med. 1985;14:568–572
  27. Miller MA, Navarro M, Bird SB, et al. Antiemetic use in acetaminophen poisoning: how does the route of N-acetylcysteine administration affect utilization?. J Med Toxicol. 2007;3:152–156
  28. Mitchell JR, Jollow DJ, Potter WZ. Acetaminophen-induced hepatic necrosis (IV. Protective role of glutathione). J Pharmacol Exp Ther. 1973;187:211–217
  29. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol. 2002;40:3–20
  30. Betten D, Cantrell F, Thomas S, et al. A prospective evaluation of shortened course oral N-acetylcysteine for the treatment of acute acetaminophen poisoning. Ann Emerg Med. 2007;50:272–279
  31. Woo OF, Mueller PD, Olson KR, et al. Shorter duration of oral N-acetylcysteine therapy for acute acetaminophen overdose. Ann Emerg Med. 2000;35:363–368
  32. Dart R, Rumack BH. Patient-tailored acetylcysteine administration. Ann Emerg Med. 2007;50:280–281
  33. Schwartz EA, Hayes BD, Samiento KF. Development of hepatic failure despite use of intravenous acetylcysteine after a massive ingestion of acetaminophen and diphenhydramine. Ann Emerg Med. doi: 10.1016/j.annemergmed.2008.10.001.
  34. Smilkstein MJ, Bronstein AC, Linden C, et al. Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol. Ann Emerg Med. 1991;20:1058–1063
  35. Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ. 1991;303:1026–1029
  36. Yip L, Dart RC, Hurlbut KM. Intravenous administration of oral N-acetylcysteine. Crit Care Med. 1998;26:40–43
  37. Kerr F, Dawson A, Whyte IM, et al. The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine. Ann Emerg Med. 2005;45:402–408
  38. Schmidt LE, Dalhoff K. Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning. Br J Clin Pharmacol. 2001;51:87–91
  39. Lynch RM, Robertson R. Anaphylactoid reactions to intravenous N-acetylcysteine: a prospective case controlled study. Accid Emerg Nurs. 2004;12:10–15
  40. Pakravan N, Waring WS, Sharma S, et al. Risk factors and mechanisms of anaphylactoid reactions to acetylcysteine in acetaminophen overdose. Clin Toxicol. 2008;46:697–702

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 Supervising editors: E. Martin Caravati, MD, MPH; Michael L. Callaham, MD

 Dr. Caravati and Dr. Callaham were the supervising editors on this article. Dr. Dart did not participate in the editorial review or decision to publish this article.

 Author contributions: RJB had the original idea for the study. MCY drafted the study protocol. DWJ, RJB, MLAS, and RFB revised the study protocol. MCY, DWJ, RJB, MLAS, and RAP obtained funding for the Canadian medical record review. BHR obtained funding for the United States National Multicenter Study. AN-A, RFB, and DAS performed the statistical analysis, and all authors contributed to the interpretation of the findings. MCY drafted the article, and all authors contributed substantially to its revision. All authors approved the final version to be published. MCY takes responsibility for the paper as a whole.

 Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. The authors disclose that unrestricted financial support for this study was received from Cumberland Pharmaceuticals, the Physicians of Ontario through the Physicians Services Incorporated Foundation, Calgary Health Region Adult Research Committee, Canadian Institutes of Health Research, Alberta Heritage Foundation for Medical Research, Canadian Association of Emergency Physicians, and the University of British Columbia Summer Student Research Program. Dr. Rumack has received honoraria and consulting fees from McNeil Consumer Products Company (Johnson & Johnson), which funded the United States National Multicenter Study on the effectiveness of oral acetylcysteine in the treatment of acute acetaminophen overdose. Dr. Dart is the Director of the Rocky Mountain Poison and Drug Center, which has received financial support from McNeil Consumer Products Company (Johnson & Johnson) and Cumberland Pharmaceuticals.

 Reprints not available from the authors.

 Publication date: Available online June 25, 2009.

PII: S0196-0644(09)00495-8

doi: 10.1016/j.annemergmed.2009.05.010

Annals of Emergency Medicine
Volume 54, Issue 4 , Pages 606-614 , October 2009