PEDIATRIC PULSE

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Acetaminophen

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.

Management

Timing of presentation determines approach:

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