Acetaminophen (APAP) overdose remains one of the most common causes of acute liver failure in the United States. While its therapeutic use is widespread and generally safe, unintentional overdoses and delayed presentations can lead to devastating outcomes. In this episode of REBEL Cast, we break down the pathophysiology, clinical course, diagnostic approach, and evidence-based management of APAP toxicity—including when to initiate NAC, how to apply the Rumack-Matthew nomogram, and the evolving role of adjunctive therapies like fomepizole. Whether you’re in the ED or elsewhere , this is core content every clinician should know.

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Definition and Physiology

• After ingestion of a therapeutic dose, immediate release APAP is absorbed with a time to peak concentration anywhere between 30-45 minutes. In the context of extended-release, formulations, full absorption is typically reached by 4 hours post-ingestion.1
• In therapeutic dosing, the vast majority of APAP undergoes hepatic conjugation with glucuronide or sulfate to form benign metabolites that ultimately get excreted in the urine. The remaining ~5% is oxidized by CYP2E1 to form N-acetyl-p-benzoquinoeimine (NAPQI). NAPQI is hepatotoxic. Glutathione combines with NAPQI to generate non-toxic metabolites that are also eliminated in the urine.
• In overdose, the amount of NAPQI that is generated is increased as the typical metabolic pathways become saturated. The NAPQI that remains leads to hepatocellular death in Zone 3 of the liver (or the centrilobular location) which is the area with the largest degree of oxidative metabolism.

Clinical Manifestations and Diagnostic Evaluation

• The clinical course of acute APAP toxicity is classically broken into four different stages.
  • Stage1: this is generally within 24 hours. Patients are either asymptomatic or have non-specific GI symptoms (nausea, vomiting, malaise). At this point, hepatic function testing is normal.
  • Stage2: ~24-72 hours. The onset of hepatic injury marks this stage. Aspartate aminotransferase (AST) is the most sensitive marker to detect hepatic dysfunction; AST elevated is nearly universal by 36 hours post-ingestion.
  • Stage3: defined as peak hepatotoxicity; generally between 72-96 hours post-ingestion. Patients may manifest hepatic encephalopathy or coma. AST and/or ALT might rise above 10,000 IU/L. Other lab abnormalities include: INR/PT, glucose, lactate, pH, and creatinine. Death from fulminant hepatic failure usually occurs anywhere between 3-5 days after an acute ingestion. Mortality is often secondary to multiorgan failure, ARDS, sepsis, or cerebral edema.
  • Stage4: often called the “recovery phase.” Patient who survive demonstrate complete hepatic generation without any evidence of hepatic dysfunction.

• The following labs should be obtained for severe APAP ingestions:
  • APAP Concentration, hepatic panel, pH, coagulation panel, renal function, lactate and phosphate. These labs will ultimately dictate disposition (see King’s College Criteria below)

Management

• Consider GI decontamination with activated charcoal as this can reduce systemic absorption and limit subsequent clinical sequalae.
• Ingestions should be classified as acute or repeated supratherapeutic (“chronic” ingestions)
  • Single Acute Ingestion
    • If feasible, obtain a 4 hour post-ingestion APAP concentration. Any concentration earlier than 4 hours is uninterpretable as subsequent concentrations may increase or decrease depending on the clinical scenario.
    • Concentrations between 4-8 hour post-ingestion can be plotted on the Rumack-Matthew nomogram to determine when NAC should be initiated.
    • If the APAP concentration is above the plotted line, NAC should be started.
      • NAC is nearly 100% effective if started within 8 hours post-ingestion.2
    • If an APAP concentration is unable to be drawn before 8 hours or if LFTs are already elevated, NAC should be empirically started if the pre-test probability is high enough for clinical concern.
  • Repeated Supratherapeutic/Chronic Ingestions
    • Cannot apply the Rumack-Matthew Nomogram
    • If LFTs are elevated or if there is a positive APAP concentration, NAC should generally be started however consultation with a toxicologist or Poison Control Center is advised as these cases are often complicated.
• N-Acetyl-Cysteine (NAC) Dosing
  • “3 Bag Protocol” – 21 hour regimen
    • 150mg/kg over 1 hour loading dose
    • 50mg/kg over 4 hours = 12.5 mg/kg/hr
    • 100mg/kg over 16 hours = 6.25 mg/kg/hr
  • Risk: anaphylactoid reaction
    • Reaction is rate related and typically occurs during the loading dose
    • Symptoms: flushing, urticaria.
  • NAC should be continued until all of the following criteria are met:
    • Negative APAP concentration
    • “Significant Decreased in AST”: defined as either <1000 IU/L or a 25-50% drop from the peak.
    • No evidence of hepatic failure
  • If criteria are not met, the third bag should be extended indefinitely.
• The King’s College Criteria should be used as this set of lab work is used to determine which patients should be referred for possible liver transplant evaluation.3, 4
  • Arterial pH < 7.30
  • INR > 6.5 (PT >100 sec)
  • Creatinine > 3.4
  • Grade III or IV hepatic encephalopathy
  • Hyperlactatemia
  • Hyperphosphatemia
• Fomepizole (traditionally used for the treatment of toxic alcohols) has been used as an adjunctive treatment for massive acetaminophen toxicity as it has demonstrated efficacy in mitigating serum transaminase elevation, hepatic necrosis, and oxidative stress in both mouse and human models.5-8
  • As large scale human studies have yet to be published, fomepizole should NOT be routinely administered for APAP toxicity.

Take Home Points

Acetaminophen (APAP), most commonly referred to as “Tylenol” in the United States, is in a variety of pharmaceuticals. Medications like Excedrin, Fioricet, Percocet, Vicodin, and Day/Nyquil all contain acetaminophen. Given the lack of a toxidrome, there should be a low threshold to obtain a screening acetaminophen concentration in the undifferentiated poisoned patient. In overdose, acetaminophen leads to generation of NAPQI which is hepatotoxic. N-Acetylcysteine (NAC) is the antidote of choice and ideally should be administered within 8 hours of an acute ingestion. To determine which patients should be treated with antidotal therapy, the Rumack-Matthew Nomogram should be utilized. Of note, this nomogram was validated for a single concentration obtained at or greater than 4 hours after a single, acute ingestion. (i.e. patients with repeated ingestions cannot be applied to the nomogram). In patients with a high pre-test probability of APAP poisoning, the King’s College Criteria should be considered; this is a set of lab markers that help determine when patients should be immediately referred for liver transplant. While physiologic plausibility exists for the use of fomepizole to treat severe APAP toxicity, no large scale human studies exist at this time to suggest that it should be routinely given for toxicity. As with all cases of toxicity, please call your local poison control center for assistance.

References

Hendrickson RG, McKeown NJ. Chapter 33. Acetaminophen. In: Nelson LS, et al., editors. Goldfrank’s Toxicologic Emergencies. 11th ed. New York: McGraw-Hill; 2019. Smilkstein MJ, Knapp GL, Kulig KW, 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):1557-1562. PMID: 3059186 O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97(2):439-445. PMID: 2490426 King’s College Criteria for Acetaminophen Toxicity. Available at: https://www.mdcalc.com/calc/532/kings-college-criteria-acetaminophen-toxicity#next-steps Akakpo JY, Ramachandran A, Duan L, et al. Delayed treatment with 4-methylpyrazole protects against acetaminophen hepatotoxicity in mice by inhibition of c-jun N-terminal kinase. Toxicol Sci. 2019;170(1):57-68. PMID: 30903181 Akakpo JY, Ramachandran A, Kandel SE, et al. 4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes. Hum Exp Toxicol. 2018;37(12):1310-1322. PMID: 29739258 Shah KR, Beuhler MC. Fomepizole as an adjunctive treatment in severe acetaminophen toxicity. Am J Emerg Med.2020;38(2):410.e5-410.e6. PMID: 31785979 Kang AM, Padilla-Jones A, Fisher ES, et al. The effect of 4-methylpyrazole on oxidative metabolism of acetaminophen in human volunteers. J Med Toxicol. 2020;16(2):169-176. PMID: 31768936

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