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)

Case:

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.

 

Treatment:

  • 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

OR

  • 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.

 

References:

  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. https://www.merckmanuals.com/professional/injuries-poisoning/poisoning/acetaminophen-poisoning. (Access 22 Aug 2017).
  4. EXTRIP. “Acetaminophen (APAP) Poisoning.” The Extracorporeal Treatments In Poisoning Workgroup. http://www.extrip-workgroup.org/acetaminophen. (Accessed 22 Aug 2017).

 

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