Acetaminophen

Written By Brandon Ho

Pathophysiology

Acetaminophen is metabolized in hepatocytes to renally cleared metabolites and toxic NAPQI (N-acetyl-p-benzoquinone imine).

  1. Normally, only small amounts of NAPQI  are made and are quickly conjugated by glutathione into a nontoxic compound

  2. In overdose, glutathione stores are exhausted leading to free NAPQI leading to oxidative injury in the liver.

Toxic doses:

  1. Acute ingestion: A single dose >150 mg/kg in children and greater than 7.5 g in adults

  2. Repeated supratherapeutic ingestion (>48h):

    1. > 200 mg/kg/day (or 10 g/day) in 24 hours OR

    2. > 150 mg/kg/day (or 6 g/day) in 48 hours OR

    3. > 100 mg/kg/day in 72 hours

Presentation

Clinical signs and symptoms of acetaminophen toxicity can be thought of as occurring in 4 distinct stages:

  1. Stage I (<24 hours): asymptomatic or vague GI symptoms. Labs are generally normal

  2. Stage II (24h-72h): Evidence of hepatic injury (RUQ pain + elevated LFTs)

  3. Stage III (72-96h):  Most deaths occur in this stage. Liver failure (jaundice, lactic acidosis, hepatic encephalopathy, coagulopathy, and AKI (hepatorenal syndrome or acute renal failure)).

  4. Stage IV (96h-2weeks): Recovery phase or complete liver failure.

Diagnosis

Consult Poison Control: 1800-222-1222

  • Obtain serum acetaminophen levels [APAP] at least 4 hrs from suspected ingestion (when absorption is likely to be complete)

    • A level performed earlier may indicate ingestion but cannot accurately assess the risk of toxicity.

    • When the time of ingestion is unknown, the earliest possible time that acetaminophen could have been taken should be used. 

    • For long-term ingestions, a level should be drawn at the time of presentation and 4 hours later

  • Screen for co-ingestions: salicylates, UDS, ethanol level

  • Blood gas & lactate POC

  • CMP, PT/PTT, lactate (but may be normal in first 24 hours from ingestion)

  • Consider CXR if concern for aspiration or AXR if concern for foreign body ingestion, battery, or radiopaque such as iron

  • Obtain EKG

Management

Timing of presentation determines approach:

  • If [APAP] is drawn at least 2 hours from the time of ingestion AND the level is undetectable, then toxic ingestion is unlikely and the patient can be discharged home with strict return precautions. Administer activated charcoal if within 2 hours post-ingestion.

    • In some cases, charcoal is indicated after the 2-hour mark. Consult with poison control for indications.

    • AVOID charcoal if AMS, unprotected airway, or co-ingestion with a corrosive or pro-convulsant substance

  • Obtain [APAP] STAT. Start IV N-acetylcysteine (NAC) antidote therapy based on Rumack-Matthew Nomogram

  • IV NAC is most effective in the first 6 to 8 hours from ingestion. If treatment will be delayed beyond this time, then NAC should be given while acetaminophen is still pending especially if signs of liver injury

  • Patients who present more than 24 hours after acute ingestion may manifest symptoms and signs of hepatic injury or failure. These cases may not have detectable [APAP]. [APAP] in this setting does not correlate with toxicity and the treatment nomogram for acetaminophen poisoning should not be used. Consider empiric treatment with NAC if:

    • If ↑ [AST], then TREAT (regardless of [APAP])

    • If detectable [APAP], then TREAT (regardless of [AST])

    • If [AST] is normal AND [APAP] is undetectable, then NO need to treat

N-acetylcysteine (NAC) antidote therapy is administered over 21 hours and has an associated risk of an anaphylactoid reaction, particularly during the initial loading dose and in patients with asthma.

  • Loading dose: IV 150mg/kg (max 15 g/dose) infuse over 1 hour

  • Second dose: 50 mg/kg (max 5 g/dose) infused over 4 hours

  • Third dose: 100 mg/kg (max 10 g/dose) infused over 16 hours 

PO form is given as a course of 18 doses over 72 hours.

  • PO 140mg/kg in the first four hours, followed by 70mg/kg every 4 hours for additional 17 doses.

If the Tylenol level is >500 consider a single dose of 15 mg/kg of fomipezole. Inhibits CYP2E1 to prevent the production of NAPQI

Indications for dialysis:

  • [APAP] >1000 mg/L (6620 μmol/L) AND NAC is NOT administered

  • AMS, metabolic acidosis, with an elevated lactate AND an [APAP] >700 mg/L (4630 μmol/L) AND NAC is NOT administered

  • AMS, metabolic acidosis, an elevated lactate AND an [APAP] >900 mg/L
    (5960 μmol/L) even if NAC is administered

Monitoring

  • Repeat labs 2 hours prior to the end of 3rd bag (CMP, acetaminophen level)

  • If [APAP] remain detectable (>10 μg/mL, LFTs increasing, or if AST >1000), then repeat the third dose of NAC

    • AST decreases before ALT, so if you have increasing ALT but down-trending AST then you are in a better place.

    • INR can be transiently  increased due to NAC, rather than worsening liver function

References

  1. Committee on Drugs. Acetaminophen Toxicity in Children. Pediatrics. 2001;108(4):1020. doi:10.1542/peds.108.4.1020

  2. Gosselin S, Juurlink DN, Kielstein JT, Ghannoum M, Lavergne V, Nolin TD; EXTRIP workgroup. (2014) "Extracorporeal treatment for acetaminophen poisoning: Recommendations from the EXTRIP workgroup." Clinical toxicology. 52(8):856-67. https://www.extrip-workgroup.org/acetaminophen

  3. Nadler A, Fein DM. Acetaminophen Poisoning. Pediatr Rev. 2018;39(6):316. doi:10.1542/pir.2017-0093

Brandon Ho
Previous

Clonidine

Next

Iron