TOXCard: Acetaminophen Toxicity and Management

Author: Maryam Abdrabbo, PharmD Candidate 2018 (Rutgers Ernest Mario School of Pharmacy, New Brunswick NJ), Cynthia Santos, MD (Assistant Professor Emergency Medicine, Medical Toxicology, Rutgers NJMS) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital), and Brit Long, MD (@long_brit, EM Attending Physician, San Antonio, TX)


A 19-year-old woman is brought into the ED by family members after she reported ingesting 35 Tylenol tablets (Extra-Strength) 2 hours ago. She complains of nausea and vomiting and admits this was an attempt to harm herself. Her weight is 54 kg.


Clinical Pearls:

Acetaminophen (APAP) comes in different strengths and formulations.

  • There are immediate- and extended-release formulations.
    • IR – majority is absorbed within 2 hours.1
    • ER – majority is absorbed within 4 hours.1
    • Therefore, one can assume for all ingested formulations (whether IR or ER), most APAP is absorbed at 4 hours.1
    • The time to peak may be extended by coingestion of opiods or anticholinergics.
  • Regular-Strength (IR) = 325mg
  • Extra-Strength (IR) = 500mg
  • Arthritis Pain 8HR (ER) = 650mg


Many OTC combination products contain acetaminophen!

  • This can be one of the causes for chronic APAP toxicities.
  • Examples include cough and cold products, migraine medications (which also could contain aspirin like Excedrin® Migraine), etc.


Acute vs. Chronic APAP Ingestion1

  • Acute overdose is arbitrarily defined as an entire ingestion within a single 8-hour period.
  • Chronic overdose occurs with repeated supratherapeutic ingestions (greater than an 8-hour period).


Toxic Dose1

  • Acute ingestion (< 8 hours)
    • Adults: 7.5 g
      • (Note: more likely to see doses >12 g cause toxicity)
    • Children: 150 mg/kg
      • (Note: more likely to see doses >200 mg/kg cause toxicity)
  • Chronic ingestion (> 8 hours)
    • Adults
      • 24-hour period
      • 200 mg/kg or 10 g (whichever is less)
      • 48-hour period
      • 150 mg/kg/day or 6 g/day (whichever is less)
    • Children
      • 100 mg/kg/day over 72 hour period or greater


Stages of Acute Acetaminophen Poisoning1,3

Getting APAP Levels1

  • Pre-4 hour vs 4-hour level
    • Getting an APAP level 1 to 4 hours after ingestion may be helpful only to exclude ingestion of APAP (that is, if the level is zero).
    • Obtain a 4-hour level (or later, up to 24 hours) to get estimated peak absorption (that is, if time of ingestion is certain).


When to Initiate Treatment:

Figure 1. Rumack-Matthew Nomogram for Acetaminophen1

Using APAP Rumack-Matthew Nomogram

  • The Rumack-Matthew nomogram is used to determine the risk of APAP-induced hepatoxicity after a single acute ingestion only (not for chronic or repeated ingestions).
  • Serum concentrations above the treatment line indicate the need for N-acetylcysteine (NAC) therapy.
  • The treatment line starts at 150 mcg/mL at 4 hours post-ingestion.
    • Remember, majority of APAP absorption occurs by 4 hours (this may not be true with overdose).

Determining Hepatotoxicity Risk if Nomogram Isn’t Applicable

  • If time of ingestion is unknown or if ingestion spans more than 24 hours: Screen with labs (APAP concentration, hepatic function tests, renal function tests, coagulation studies, blood gas), assess patient risk factors and clinical features.1,3
    • If ASTs are elevated = treat with NAC
    • If [APAP] is detectable = treat with NAC
    • If [APAP] is undetectable and ASTs are normal = NAC is unnecessary
    • If lab testing shows progressive hepatic failure or continued detection of [APAP] = continue NAC (this implies repeat testing).


Laboratory Assessment:

  • APAP Levels
  • Assess Labs for Hepatic Injury
    • Get initial and daily LFTs
      • If progressive hepatic failure, obtain LFTs every 12 hours
    • PT, INR
    • pH (Metabolic acidosis)
    • SCr (Toxic APAP metabolites can also affect CYP enzymes in the kidney)
  • Continue Lab Monitoring

This patient plots above the “150-line” at 4 hours on the nomogram for her single ingestion acute overdose. She should be started on NAC. Continue monitoring the patient’s labs.



  • GI decontamination
    • Generally not useful due to rapid APAP absorption
    • Activated charcoal may be useful if administered early on or if suspected co-ingestants
  • Supportive care
    • Nausea, vomiting, acidosis, hepatic or renal failure
  • Antidotal therapy with N-Acetyl Cysteine (NAC)
    • Best and most effective option!


N-Acetyl Cysteine (NAC) Therapy1,2

Mechanism of Action:

  • The non-toxic route of APAP metabolism gets saturated in overdoses, which leads to the formation of the toxic metabolite NAPQI.
  • NAC helps replenish glutathione stores to conjugate the toxic metabolite, and assists with other routes of liver metabolism as well. See Figure 2 below.

Figure 2.1  NAC has a hepatoprotective effect. NAC augments sulfation, NAC2 is a glutathione (GSH) precursor, NAC3 is a GSH substitute, and NAC4 improves multiorgan function during hepatic failure and possibly limits the extent of hepatocyte injury.


NAC Dosing:1,2

Treatment should begin within 8 hours of ingestion or as soon as possible after ingestion.

  • Oral (Mucomyst®):
    • 72-hour regimen: Consists of 18 doses
      • Loading dose: 140 mg/kg
      • Maintenance dose: 70 mg/kg every 4 hours for 17 additional doses
    • Repeat dose if emesis occurs within 1 hour of administration
  • IV (Acetadote ®):
    • 21-hour regimen: Consists of 3 components
      • Loading dose: 150 mg/kg infused over 1 hour
      • Second dose: 50 mg/kg infused over 4 hours
      • Third dose: 100 mg/kg infused over 16 hours

Note: It is highly recommended to consult with a poison control center or medical toxicologist when considering the discontinuation of acetylcysteine prior to the conclusion of a full course of therapy.


Liver Transplant1

King’s College Criteria for predicting the need for hepatic transplant:

  • Serum pH < 7.3 or lactate > 3 mmol/L after fluid resuscitation


  • All of the following:
    • SCr > 3.3 mg/dL
    • PT > 100 sec (or INR > 6.5)
    • Grade III or IV encephalopathy


Main Point:

  • For patients with acute APAP overdoses, use the Rumack-Matthew Nomogram.
    • Plot a single [APAP] onto the nomogram.
    • If the [APAP] plots above the treatment line, or “150-line”, treat with NAC.
  • For patients with chronic APAP overdoses (repeated supratherapeutic ingestions), treat with NAC if:
    • ASTs are elevated OR [APAP] is detectable.
  • Use the King’s College Criteria for evaluating the need for hepatic transplantation.
  • NAC shouldn’t be given as a set length protocol. An informed decision should be made when stopping NAC, which requires assessing that the risk of developing toxicity is low ([APAP] is undetectable, ASTs are normal), and any toxicity that occurred has been resolved.



  1. Hendrickson RG. Acetaminophen. In: Goldfrank’s Toxicologic Emergencies 9th edition. Nelson LS, et al (Eds). New York, NY, McGraw-Hill 2011.
  2. Acetylcysteine [monograph]. In: Lexicomp Online [online database]. Hudson, OH: Lexi-Comp (Accessed 2017 Aug 22).
  3. O’Malley GF., Kimmel S, O’Malley R. “Acetaminophen Poisoning.” Merck Manuals Professional Edition. (Access 22 Aug 2017).
  4. EXTRIP. “Acetaminophen (APAP) Poisoning.” The Extracorporeal Treatments In Poisoning Workgroup. (Accessed 22 Aug 2017).


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