Skip to main content

Main menu

  • Home
  • Articles
    • Current
    • Published Ahead of Print
    • Archive
    • Supplemental Issues
    • Collections - French
    • Collections - English
  • Info for
    • Authors & Reviewers
    • Submit a Manuscript
    • Advertisers
    • Careers & Locums
    • Subscribers
    • Permissions
  • About CFP
    • About CFP
    • About the CFPC
    • Editorial Advisory Board
    • Terms of Use
    • Contact Us
  • Feedback
    • Feedback
    • Rapid Responses
    • Most Read
    • Most Cited
    • Email Alerts
  • Blogs
    • Latest Blogs
    • Blog Guidelines
    • Directives pour les blogues
  • Mainpro+ Credits
    • About Mainpro+
    • Member Login
    • Instructions
  • Other Publications
    • http://www.cfpc.ca/Canadianfamilyphysician/
    • https://www.cfpc.ca/Login/
    • Careers and Locums

User menu

  • My alerts

Search

  • Advanced search
The College of Family Physicians of Canada
  • Other Publications
    • http://www.cfpc.ca/Canadianfamilyphysician/
    • https://www.cfpc.ca/Login/
    • Careers and Locums
  • My alerts
The College of Family Physicians of Canada

Advanced Search

  • Home
  • Articles
    • Current
    • Published Ahead of Print
    • Archive
    • Supplemental Issues
    • Collections - French
    • Collections - English
  • Info for
    • Authors & Reviewers
    • Submit a Manuscript
    • Advertisers
    • Careers & Locums
    • Subscribers
    • Permissions
  • About CFP
    • About CFP
    • About the CFPC
    • Editorial Advisory Board
    • Terms of Use
    • Contact Us
  • Feedback
    • Feedback
    • Rapid Responses
    • Most Read
    • Most Cited
    • Email Alerts
  • Blogs
    • Latest Blogs
    • Blog Guidelines
    • Directives pour les blogues
  • Mainpro+ Credits
    • About Mainpro+
    • Member Login
    • Instructions
  • RSS feeds
  • Follow cfp Template on Twitter
OtherPractice

How much did you take?

Reviewing acetaminophen toxicity

Jesse Janssen and Sanjeet Singh-Saluja
Canadian Family Physician April 2015, 61 (4) 347-349;
Jesse Janssen
Emergency medicine fellow in the Family Medicine Enhanced Skills Program at McGill University in Montreal, Que.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sanjeet Singh-Saluja
Emergency medicine physician in the Department of Family and Emergency Medicine at McGill University.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • eLetters
  • Info & Metrics
  • PDF
Loading

Case descriptions

Case 1

A 45-year-old woman presents to your emergency department asking for help. She took 18 extra-strength (500-mg) acetaminophen (APAP) tablets approximately 5 hours ago in an attempt to end her life. She denies taking any other medications and is otherwise healthy. She realizes that she made a mistake and is asking for your help. Her vital signs are stable, examination findings are normal, and she looks well. Her APAP level is 1300 µmol/L (200 mg/L).

Case 2

A 52-year-old man with known depression and a history of suicide attempts was last seen by his friend picking up a bottle of 150 extra-strength APAP tablets for his chronic back pain. Another friend visits approximately 1.5 hours later and finds the man to be somnolent, difficult to rouse, and confused, and the bottle of APAP is empty. He calls 911. The man presents to the hospital with a Glasgow Coma Scale score of 6, a blood pressure of 100/80 mm Hg, and a heart rate of 100 beats/min. Results of preliminary bloodwork, drawn 4 hours after the purchase of the APAP, reveal a pH of 7.0, a lactate level of 15 mmol/L, and an APAP level of 6620 µmol/L (1000 mg/L).

Acetaminophen toxicity is the leading cause of acute liver failure in Canada.1 When recognized within 8 hours of ingestion and treated with its antidote, N-acetylcysteine (NAC), morbidity and mortality are rare.2 In an effort to promote appropriate risk assessment and avoid overtreatment, we aim to clarify some misconceptions with respect to the identification and treatment of APAP toxicity.

Pathophysiology and mechanisms

Acetaminophen is well absorbed through the gut, with peak serum levels being reached within 2 hours of ingestion; however, this time frame might be prolonged if APAP is taken with other medications that alter gut motility or if it is taken in a delayed-release preparation.3

Acetaminophen toxicity stems from saturation of its usual hepatic metabolism mechanisms: sulfation and glucuronidation. When these mechanisms are overrun, the cytochrome P450 system is funnelled more APAP to metabolize. It creates the hepatotoxic metabolite known as N-acetyl-p-benzoquinoneimine (NAPQI). Glutathione in the liver helps to reduce NAPQI to a safe renally excretable metabolite. In APAP toxicity, glutathione’s reduction capabilities are overwhelmed, leaving NAPQI free in the liver.3,4

Presentation

Doses leading to APAP toxicity are described in Box 1.5 Symptoms of toxicity are classically described in 4 phases:

  • The first 24 hours are marked by nonspecific symptoms including nausea, vomiting, and malaise.

  • Between 24 and 72 hours, hepatotoxicity with right upper-quadrant tenderness develops.

  • Starting 3 to 4 days after ingestion, there is a progression to fulminant hepatic failure, including encephalopathy, coagulopathy, and multiorgan failure.

  • The fourth phase starts on day 5 and is a turning point—patients either start improving and have complete recovery, or they progress to multiorgan failure and death.3,6

Box 1.

Therapeutic and toxic doses of acetaminophen

Therapeutic dose
  • 60 mg/kg daily, divided into 3 or 4 doses, no greater than 4 g/d


Single-ingestion hepatotoxic dose
  • 200 mg/kg or 10 g (whichever is less)


Repeated supratherapeutic ingestion
  • Over a 24-h period: 200 mg/kg or 10 g/d (whichever is less)

  • Over a 48-h period: 150 mg/kg or 6 g/d (whichever is less)

  • If risk factors are present (alcoholism, prolonged fasting, isoniazid use): 100 mg/kg daily or 4 g/d

  • For children younger than 6 y, same as above, but if over a 72-h period or longer: 100 mg/kg daily

  • Data from Dart et al.5

  • This changes in the context of massive ingestion (> 500 mg/kg), in which patients present with altered mental status and marked lactic acidosis. These symptoms present within 12 hours of ingestion and are thought to be secondary to mitochondrial dysfunction.2

    Treatment

    All treatment decisions should start with a risk assessment including identifying what agents were ingested, the doses, the time since ingestion, clinical features, and patient factors such as weight and comorbidities. Furthermore, early consultation with your regional poison control centre should always be considered.

    While NAC is the antidote to the hepatotoxic effects of APAP metabolites, it does not affect APAP levels.3 It can be given orally, but it is usually given intravenously in 3 staggered doses: a 150 mg/kg bolus, a 50 mg/kg dose over 4 hours, and a 100 mg/kg dose over 16 hours. The most common reaction is a mild anaphylactoid reaction that results in flushing, rash, and angioedema. It can be treated with antihistamines while continuing the infusion. The infusion should be stopped only if the reaction is deemed severe. It should be restarted once symptoms settle.3

    Because NAC is so effective in cases in which the patient presents early, the role for activated charcoal is minimal. Nevertheless, it can decrease the need for NAC in fully oriented patients who present within 1 to 2 hours of ingestion. It is also appropriate for massive ingestions in which patients are already intubated. There is no role for ipecac in anyone, and charcoal is not recommended in children younger than 6 years of age regardless of the time of presentation.7

    Treatment with NAC is initiated based on the Rumack-Matthew nomogram, which delineates treatment thresholds based on APAP levels between 4 and 24 hours after ingestion. It uses 1000 µmol/L (150 mg/L) as the initial “treatment line” at 4 hours.8

    If the patient presents within 8 hours of ingestion, there are no suspected co-ingestions, and there is no indication of massive overdose, an APAP level measured between 4 and 8 hours after ingestion is all that is needed. Liver function tests do not help risk assessment or prognostication any further. Patients who present within this window and have APAP levels above the threshold can be treated without further testing. In this setting, if NAC is started within this time frame there is universal survival.7 If levels are not available within the 8 hours, it is prudent to start NAC, as it can always be stopped.

    Patients presenting between 8 and 24 hours after ingestion should be immediately started on NAC while awaiting results of APAP measurement. With this delay in treatment, measurement of alanine aminotransferase (ALT) is also recommended. Measurement of APAP and ALT levels should be repeated at the end of NAC treatment. If the APAP level is decreasing and the ALT level is within the normal range, no further treatment is required. If not, continue the NAC and obtain creatinine, glucose, arterial blood gas, and coagulation studies, including international normalized ratio, for hepatic transplant risk stratification.7

    The nomogram is no longer applicable for patients presenting more than 24 hours after ingestion. Treatment with NAC should be started and APAP, ALT, creatinine, arterial blood gas, glucose, and creatinine levels and international normalized ratio should be measured. If laboratory findings are normal, no further treatment is required; if ALT levels are abnormal, NAC is continued for the full protocol.7

    With repeated supratherapeutic ingestion, patients with APAP levels below 66 µmol/L (10 mg/L) and ALT or aspartate aminotransferase levels below 0.83 µkat/L (50 U/L) require no further workup or treatment. In all other patients, NAC should be started and the extended workup described above should be conducted for risk stratification. After 8 hours of NAC treatment, measurement of the ALT level should be repeated; if it is stagnant or decreasing, NAC can be discontinued. If it is rising, NAC should be continued and the patient should be assessed for possible admission to intensive care or for appropriateness for hepatic transplant.7,9

    Appropriateness for hepatic transplant is traditionally based on the King’s College Criteria; however, these criteria have been criticized for lacking sensitivity and for missing patients who might benefit from liver transplant. The APACHE II (Acute Physiology and Chronic Health Evaluation II) score has been suggested as an alternative, but it has yet to be evaluated in this context.10

    While it has not been well studied, hemodialysis has been recommended as the treatment of choice for massive ingestions in which NAC alone might not be enough. An APAP level greater than 6620 µmol/L (1000 mg/L) without symptoms, or signs of mitochondrial dysfunction with an APAP level greater than 4630 µmol/L (700 mg/L) without NAC or greater than 5960 µmol/L (900 mg/L) with NAC are the current indications for this strategy.2

    Pearls

    • If ingestion involves numerous doses within an 8-hour period, total the dose and base the APAP level on the nomogram for the earliest dose taken.

    • If capsules are extended release and the dose is 150 mg/kg or more, start NAC and then discontinue it if APAP levels end up being below the 4- and 8-hour thresholds.

    Case resolutions

    Case 1

    The patient is given a 21-hour treatment with NAC, is seen by a psychiatrist, and is discharged home safely with outpatient mental health follow-up.

    Case 2

    The patient is thought to be experiencing a massive overdose of APAP. Owing to his level of consciousness, he is intubated. Once his airway is secure, he is given activated charcoal and NAC is started immediately. His history, medication record, physical examination and electrocardiogram findings, and bloodwork results are reviewed for other potential causes of his altered mental status. His case is reviewed with the regional toxicologist who recommends a trial of dialysis. Despite aggressive resuscitation efforts, he does not survive his massive ingestion.

    Notes

    BOTTOM LINE

    • When a patient presents with potential acetaminophen (APAP) toxicity, always perform a risk assessment including identifying what agents were ingested, the doses, the time since ingestion, clinical features, and patient factors such as weight and comorbidities.

    • If the APAP was ingested within the past 8 hours and there were no co-ingestions, only the initial APAP level is needed to decide whether to initiate treatment with N-acetylcysteine (NAC). When the time of ingestion is unclear, or was longer than 8 hours ago, additional workup is required. If it has been longer than 24 hours since ingestion, or if staggered doses were taken over more than 8 hours, the Rumack-Matthew nomogram cannot be used to determine the treatment threshold; treatment must be based on APAP and alanine aminotransferase levels.

    • If NAC is started before initial APAP levels are available, it is safe to stop it if results of initial testing subsequently indicate no need for treatment.

    • Massive ingestion (> 500 mg/kg) of APAP presents early with altered mental status and lactic acidosis before liver injury; along with NAC treatment, these patients might require dialysis.

    POINTS SAILLANTS

    • Lorsqu’un patient se présente avec une intoxication potentielle à l’acétaminophène, on doit toujours procéder à une évaluation des risques, y compris la détermination des substances ingérées, des doses, du temps écoulé depuis l’ingestion, des paramètres cliniques et des facteurs inhérents au patient tels que son poids et ses comorbidités.

    • Si l’acétaminophène a été ingéré au cours des 8 dernières heures et qu’il n’y a eu aucune autre ingestion simultanée, seul le niveau d’acétaminophène initial est nécessaire pour déterminer si un traitement à la N-acétylcystéine(NAC) est requis. Lorsque le moment de l’ingestion est imprécis ou s’est produit plus de 8 heures avant l’intervention, une investigation supplémentaire est nécessaire. S’il s’est écoulé plus de 24 heures depuis l’ingestion ou si des doses ont été prises progressivement dans un intervalle de plus de 8 heures, le nomogramme de Rumack-Matthew ne peut pas être utilisé pour déterminer le seuil thérapeutique; le traitement doit être basé sur les niveaux d’acétaminophène et d’alanine aminotransférase.

    • Si le traitement à la NAC a débuté avant que les niveaux d’acétaminophène aient été déterminés, il est sécuritaire de cesser le traitement si les tests initiaux indiquent subséquemment qu’un traitement n’était pas nécessaire.

    • Les patients qui font une ingestion massive (>500 mg/kg) d’acétaminophène présentent rapidement une altération de l’état mental et une acidose lactique avant la survenance d’une lésion hépatique; ils peuvent nécessiter une dialyse en plus d’un traitement à la NAC.

    Footnotes

    • Competing interests

      None declared

    • Copyright© the College of Family Physicians of Canada

    References

    1. 1.↵
      1. Government of Canada [website]
      . Acetaminophen. Ottawa, ON: Government of Canada; 2012. Available from: www.healthycanadians.gc.ca/drugs-products-medicaments-produits/drugs-medicaments/acetaminophen-eng.php?_ga=1.17764345.1568379196.1417016904. Accessed 2015 Jan 17.
    2. 2.↵
      1. Gosselin S,
      2. Juurlink DN,
      3. Kielstein JT,
      4. Ghannoum M,
      5. Lavergne V,
      6. Nolin T,
      7. et al
      . Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP Workgroup. Clin Toxicol (Phila) 2014;52(8):856-67. Epub 2014 Aug 18.
      OpenUrlCrossRefPubMed
    3. 3.↵
      1. Hung O,
      2. Nelson L
      . Acetaminophen. In: Tintinalli J, editor. Tintinalli’s emergency medicine. 7th ed. Toronto, ON: McGraw Hill; 2011. p. 1246-52.
    4. 4.↵
      1. Ogilvie JD,
      2. Rieder MJ,
      3. Rodrick L
      . Acetaminophen overdose in children. CMAJ 2012;184(13):1492-6. Epub 2012 Jun 4.
      OpenUrlFREE Full Text
    5. 5.↵
      1. Dart RC,
      2. Erdman AR,
      3. Olson KR,
      4. Christianson G,
      5. Manoguerra AS,
      6. Chyka PA,
      7. et al
      . Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2006;44(1):1-18.
      OpenUrlPubMed
    6. 6.↵
      1. Murray L,
      2. Daly F,
      3. Little M,
      4. Cadogan M
      , editors. Handbook of toxicology. 2nd ed. New York, NY: Elsevier; 2011. Paracetamol: acute toxicity; p. 302-11.
    7. 7.↵
      1. Daly FF,
      2. Fountain JS,
      3. Murray L,
      4. Graudins A,
      5. Buckley NA,
      6. Panel of Australian and New Zealand clinical toxicologists
      . Guidelines for the management of paracetamol poisoning in Australia and New Zealand—explanation and elaboration. Med J Aust 2008;188(5):296-301.
      OpenUrlPubMed
    8. 8.↵
      1. Smilkstein MJ,
      2. Knapp GL,
      3. Kulig KW,
      4. Rumack BH
      . 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(24):1557-62.
      OpenUrlCrossRefPubMed
    9. 9.↵
      1. Daly FF,
      2. O’Malley GF,
      3. Heard K,
      4. Bogdan GM,
      5. Dart RC
      . Prospective evaluation of repeated supratherapeutic acetaminophen (paracetamol) ingestion. Ann Emerg Med 2004;44(4):393-8.
      OpenUrlCrossRefPubMed
    10. 10.↵
      1. Bailey B,
      2. Amre DK,
      3. Gaudreault P
      . Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med 2003;31(1):299-305.
      OpenUrlCrossRefPubMed
    PreviousNext
    Back to top

    In this issue

    Canadian Family Physician: 61 (4)
    Canadian Family Physician
    Vol. 61, Issue 4
    1 Apr 2015
    • Table of Contents
    • About the Cover
    • Index by author
    Print
    Download PDF
    Article Alerts
    Sign In to Email Alerts with your Email Address
    Email Article

    Thank you for your interest in spreading the word on The College of Family Physicians of Canada.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    How much did you take?
    (Your Name) has sent you a message from The College of Family Physicians of Canada
    (Your Name) thought you would like to see the The College of Family Physicians of Canada web site.
    CAPTCHA
    This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
    Citation Tools
    How much did you take?
    Jesse Janssen, Sanjeet Singh-Saluja
    Canadian Family Physician Apr 2015, 61 (4) 347-349;

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
    Respond to this article
    Share
    How much did you take?
    Jesse Janssen, Sanjeet Singh-Saluja
    Canadian Family Physician Apr 2015, 61 (4) 347-349;
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
    • Tweet Widget
    • Facebook Like
    • Google Plus One

    Jump to section

    • Article
      • Case descriptions
      • Pathophysiology and mechanisms
      • Presentation
      • Treatment
      • Pearls
      • Case resolutions
      • Notes
      • Footnotes
      • References
    • Figures & Data
    • Info & Metrics
    • eLetters
    • PDF

    Related Articles

    • No related articles found.
    • PubMed
    • Google Scholar

    Cited By...

    • No citing articles found.
    • Google Scholar

    More in this TOC Section

    Practice

    • Is 45 the new 50 in colorectal cancer screening?
    • Approach to diagnosis and management of childhood attention deficit hyperactivity disorder
    • Determining if and how older patients can safely stay at home with additional services
    Show more Practice

    Emergency Files

    • Inhalation injury
    • Can you hear me?
    Show more Emergency Files

    Similar Articles

    Navigate

    • Home
    • Current Issue
    • Archive
    • Collections - English
    • Collections - Française

    For Authors

    • Authors and Reviewers
    • Submit a Manuscript
    • Permissions
    • Terms of Use

    General Information

    • About CFP
    • About the CFPC
    • Advertisers
    • Careers & Locums
    • Editorial Advisory Board
    • Subscribers

    Journal Services

    • Email Alerts
    • Twitter
    • RSS Feeds

    Copyright © 2023 by The College of Family Physicians of Canada

    Powered by HighWire