December 30, 2025
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emDOCs Revamp: Acetaminophen Toxicity – emDocs

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emDOCs Revamp: Acetaminophen Toxicity – emDocs


Authors: Rachel Bridwell, MD (EM Attending Physician; Charlotte, NC); Kyler Osborne, MD (EM Attending Physician; Clarksville, TN); Katey DG Osborne, MD (EM Attending Physician; Clarksville, TN) // Reviewed by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital); Brit Long, MD (@long_brit, EM Attending Physician, UVA)

Welcome to emDOCs revamp! This series provides evidence-based updates to previous posts so you can stay current with what you need to know.

A 17 year-old male with a history of anxiety and major depressive disorder presents to the emergency department following a suicide attempt by toxic ingestion. The patient reports consumption of approximately fifty 500 mg Tylenol caplets 90 minutes prior to arrival. The patient is nauseated and covered in non-bloody gastric contents after multiple bouts of emesis. Upon initial examination: GCS 15. VS: HR 132, BP 128/84, RR 22, SpO2 98% on room air.

General: alert and oriented though appears uncomfortable
Eyes: No scleral icterus
Pulm: Tachypneic, no wheezes or rhonchi
Cardiovascular: Tachycardia
Abdomen: Soft, diffusely uncomfortable, non-peritonitic
Skin: No evidence of jaundice or petechiae

What is the patient’s diagnosis? What’s the next step in your evaluation and treatment?

 

Answer: Acute Acetaminophen Toxicity1-41

Epidemiology

  • Most commonly used analgesic1
  • Acetaminophen is the most common cause for acute liver failure in the U.S. 1
    • 300,000 admissions annually for acetaminophen induced hepatotoxicity and 6% of patients are prescribed >4g/day2
  • 52% of ingestions are intentional while 48% are accidental, though both groups equally contribute to hepatotoxicity admissions and transplant referrals2,3
    • 29% of acute ingestions undergo liver transplantation with an associated 28% mortality rate4
  • Chronic alcohol use is mildly protective against acute acetaminophen toxicity1
  • Worsened by chronic liver disease, advancing age, malnutrition, ingestion of herbs and plants that cause reduced glucuronidation1

 

Pathophysiology:

  • Acetaminophen toxic ingestion5:
    • >10 g or >150-200 mg/kg in single ingestion over 24 hours OR:
    • >6g or >150 mg/kg per 24 hours for 2 days OR:
    • 200 mg/kg in healthy pediatric patients from 1-6 years old
  • As a weak acid, absorption occurs in the duodenum; mildly delayed if an extended release formulation, coingestion with anticholinergics (e.g. diphenhydramine), in those with chronic liver failure, and if consumed with food6
  • Metabolism occurs at the hepatic microsomal level
    • Majority (~90%) eliminated via glucuronidation and excreted via urine6
    • 2% is excreted unmetabolized6
    • Minority (~8-10%) shunted to metabolism via CYP2E1 to undergo phase I oxidation, producing N-acetyl-para-benzo-quinone imine (NAPQI)7,8
      • NAPQI is highly hepatotoxic7,8
        • Depletes glutathione
        • Generates oxidative stress via free radical production
        • Depletes ATP stores
        • Causes mitochondrial stress
          • The mitochondrion is the powerhouse of the cell

 

Clinical Presentation:

  • Stage 1: 0-24 hours: nonspecific symptoms with nausea, vomiting, lethargy1
    • AST and ALT can start to rise as early as 8-12 hours1
    • In massive overdose, acidosis, coma, and shock can present during this typically asymptomatic phase9
  • Stage 2: 24-72 hours: Latent period, resolution of stage 1 symptoms, may see RUQ tenderness in large ingestions1
    • AST and ALT more typically rise during this period1
    • Acute renal failure 2/2 ATN occurs in 1-2% of patients10
  • Stage 3: 72-96 hours: Return of stage 1 symptoms plus jaundice, encephalopathy, acute renal failure, lactic acidosis, and coagulopathy
    • As a component of King’s College criteria, lactic acidosis carries poor prognosis11
    • Prothrombin time >180s and/or an increase of >4s after the peak of toxicity per APAP levels confers a 90% mortality without transplantation12
  • Stage 4: 96 hours- 2weeks: recovery stage but duration depends on severity of ingestion; chronic hepatitis is not known to be a complication of acetaminophen ingestion4
    • Stages 3-4 are the periods of most severe manifestation of multiorgan dysfunction1

 

Evaluation:

  • History if it can be obtained is key to determine ingested substances, quantity, and timing
  • Co-ingestion with diphenhydramine for Tylenol PM formulations may also present with an anticholinergic toxidrome or with opioid toxidrome with oxycodone compounding1,13
    • Decreased, stagnant gut motility increases duration of enteral transit of acetaminophen13
  • Thorough physical exam
    • HEENT: Scleral icterus later in presentation (stage 2-3)4
    • CV: Tachycardia
    • GI: Abdominal tenderness especially RUQ 2/2 hepatic edema and capsular stretch, though hepatomegaly not usually seen since 2/2 hepatocellular necrosis14,15
    • Integumentary: Jaundice later in presentation, can inspect sublingually in patients with darker skin tones (stage 2-3)4
    • Neuro: Encephalopathy seen at stage 2-3, especially concerning for cerebral edema, seen in 89% of acetaminophen toxicity with encephalopathy with significant increased risk for herniation, will often occur early 2/2 metabolic acidosis prior to hepatotoxicity as well as later 2/2 hyperammonemia16–18
      • Drowsiness, coma, lethargy, and agitation are all associated with mortality and poor outcomes (OR 23.95)19
  •  Labs
    • Complete Blood Count: non specific but may see leukocytosis with increased neutrophil to lymphocyte ratio in the acute setting
    • Basic Metabolic Panel: may demonstrate acute renal failure1
    • Liver Associated Enzymes: elevations in AST and ALT may occur as early as stage 1, but occur in stage 2 typically1
      • Acetaminophen toxicity is one of the few causes that can increase AST and ALT to >10,000 IU/L
    • Acetaminophen Level: obtain for all ingestions
      • Plot level on Revised Rumack-Matthew Nomogram (see below)
    • PT/INR, PTT: will demonstrate coagulopathy during stage 31
    • Ethanol Level, and Salicylate Level: assesses for common ingestion, polysubstance
    • Urine Drug Screen– variable utility
  • ECG
    • Non-specific, may reveal tachycardia, bradycardia, or evidence of ischemia
      • Tachycardia may occur as a manifestation of hepatoxicity20,21
      • Bradycardia was associated with major negative outcomes or death (OR 2.29), likely reflecting underlying pathophysiologic state19
      • Ischemic changes including ST changes and T wave inversions represent global oxidative stress with cardiac effects rather than intrinsic isolated cardiotoxicity from acetaminophen22,23
  •  Imaging: None intrinsic to this ingestion
    • Non contrasted head CT would be appropriate for any presentation of altered mental status, though very low yield in toxic ingestions24
    • Chest radiograph if concern for aspiration pneumonitis
  • Rumack Matthew Nomogram: applies to acute, single ingestions only25
    • Risk for hepatic failure – ‘Treatment line’ on Nomogram
      • A level >150 ug/mL at 4 hours
      • Any level above this line should prompt intervention
    • Significant risk for hepatic failure – ‘High-Risk line’ on Nomogram
      • A level >300 ug/mL at 4 hours
      • A level >150 ug/mL at 8 hours
    • Co-ingestions: Anticholinergic or opioids may delay acetaminophen absorption
      • If a level measured 4-24 hours after ingestion is>10 μg/mL (but less than treatment line) and clinical findings are concerning for anticholinergic or opioid effects, another level should be obtained 4-6 hours after the first

matthew rumack

Revised Rumack-Matthew Nomogram for acute acetaminophen ingestion.25

 

Treatment:

  • Address ABCs, with consideration that acetaminophen toxicity may require advanced airway management
  • Call poison control early: 1-800-222-1222
  • N-acetyl cysteine (NAC)
    • Administration
      • Use published protocol with regimen that delivers 300 mg/kg over 20-24 hours
      • If >30 grams were ingested, or level will not return for 8 hours, start NAC
      • If loading dose of 150 mg/kg is to be used, give over at least one hour
    • Regular dosing26
      • IV and oral regimens available, though IV tolerated better
      • IV Dosing:
        • Stage 1 – Loading dose
        • Stage 2 – Maintenance dose #1
        • Stage 3 – Maintenance dose #2
          • 100 mg/kg over 16 hours (or until discontinuation criteria met)
      •  Oral Dosing: (total of 72 hours, 18 doses)
        • Loading dose
        • Maintenance dose
          • 70 mg/kg given every 4 hours, for 17 total doses
    •  Anaphylactoid reactions occur in 8-16% of patients receiving IV NAC, more commonly occurring in the 3 bag protocol over a 2 bag protocol27
      • Most commonly presents within 30-60 minutes of administration with28,29:
        • Facial flushing (6-1-6.7%)
        • Urticaria (4.1-4.3%)
        • Respiratory difficulties (1.9-2.2%)
        • Anaphylaxis and hypotension (0.1%)
      • If symptoms are limited to the integumentary system, slow infusion and treat with IV diphenhydramine30
      • If bronchospasm, angioedema, hypotension, or anaphylaxis occur, stop infusion and treat with IM epinephrine and diphenhydramine30
  •  High risk ingestions require increased NAC dosing to mitigate worse outcomes despite standard dosing9
    • High risk ingestions9
      • 30 g ingestion
      • Acetaminophen level of > 300 ul/mL at 4 hours
      • Acetaminophen level of > 150 ul/mL at 8 hours
  •  Harbingers of poorer outcomes in high risk ingestions despite standard NAC dosing 9:
    • AST and ALT > 1000 u/L
    • Evidence of hyperacute hepatic failure within 72-96 hours of ingestion
      • Requirement for renal replacement therapy
      • Cerebral edema
      • Fulminant hepatic failure
    •  Dosing
      • First and second dose unchanged
      • Third dose: 200 mg/kg IV over 16 hours
        • Targets need to increase glutathione stores
          • Do not bolus quickly, case reports of cerebral edema31
    •  NAC Discontinuation Criteria25
      • Acetaminophen level <10 ug/mL
      • INR < 2
      • ALT/ AST at patient baseline; if elevated has decreased from peak levels by at least 25-50%
      • Clinically well-appearing patient
  •  Fomepizole: more recent adjunct in treatment of acetaminophen toxicity, especially in larger ingestions32
    • Proposed mechanisms of action
      • CYP2E1 inhibition, reducing NAPQI production from acetaminophen33,34
      • Inhibition of c-Jun-N-terminal kinase (JNK)35
        • JNK increases mitochondrial permeability and oxidative stress, generating further hepatoxicity35
        • Fomepizole inhibits ATP binding, preventing damage secondary to reactive oxygen species35
    •  Indications for administration: high risk of hepatotoxicity
      • ALT multiplication product (ALT x acetaminophen level)>10,000 mg/L x IU/L36
      • Chronic ethanol use suggesting chronically upregulated CYP2E137
      • Delay in NAC administration exceeding 8 hours37
        Serum acetaminophen half-life > 4 hours38
      • Massive acetaminophen ingestions with levels> 600 mcg/mL39
    • Dosing:
      • No set dosing disparate from toxic alcohol
      • 15 mg/kg load over 30 minutes and 10 mg/kg q12 hours until acetaminophen levels undetectable32,40
  • Renal replacement therapy41
    • Acetaminophen easily dialyzed off, but NAC is far cheaper and easier in terms of administration, making it first line
    • Indications
      • Without NAC administration
        • Acetaminophen levels > 1000 ug/uL
        • Acetaminophen levels > 700 ug/uL and altered mental status, elevated lactate, and acidemia
      • Despite NAC administration
        • Acetaminophen levels > 900 ug/uL and altered mental status, elevated lactate, and acidemia
      • Do not administer based on reported ingestion amount, with or without NAC administration
      • iHD preferred but CRRT is acceptable
  • Transplant referral: early consideration and transfer in order to best support UNOS listing
    • King’s College Criteria11
    • Discuss with liver transplant center for any of the following:
      • pH<7.3
      • INR>6.5, PT>100 sec
      • Cr>3.4 mg/dL
      • Grade III-IV hepatic encephalopathy
    • Also consider with:
      • Lactate> 3.5 mmol/L after full fluid resuscitation (<4hr) or >3 after full fluid resuscitation (>12 hours)
      • Phosphate>3.75 mg/dL at 48-72 hours

 

Disposition

  • Consult poison control (1-800-222-1222)
  • NAC protocol will require admission
  • ICU level care with potential transfer required for many indications, especially in super-toxicity

 

Pearls/Pitfalls:

  • Coingestions may complicate clinical presentation given multiple acetaminophen formulations with opiates and anticholinergics which may cause “line jumping”
  • Utilize Rumack-Matthew nomogram for acute, 1 time ingestions, though understand the 2 competing curves of LAEs vs acetaminophen toxicity
  • Transfer to liver transplant center may be necessary under consideration of King’s College Criteria, significantly reducing mortality
  • Consider if this is super ingestion to discuss with toxicology for high dose NAC, fomepizole, and HD which may require transfer

 

References:

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  2. Blieden M, Paramore LC, Shah D, Ben-Joseph R. A perspective on the epidemiology of acetaminophen exposure and toxicity in the United States. Expert Rev Clin Pharmacol. 2014;7(3):341-348. doi:10.1586/17512433.2014.904744
  3. Herndon CM, Dankenbring DM. Patient perception and knowledge of acetaminophen in a large family medicine service. J Pain Palliat Care Pharmacother. 2014;28(2):109-116. doi:10.3109/15360288.2014.908993
  4. Bunchorntavakul C, Reddy KR. Acetaminophen-related Hepatotoxicity. Clin Liver Dis. 2013;17(4):587-607. doi:10.1016/j.cld.2013.07.005
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  37. Shah KR, Beuhler MC. Fomepizole as an Adjunctive Treatment in Severe Acetaminophen Toxicity. Am J Emerg Med. 2020;38(2):410.e5-410.e6. doi:10.1016/J.AJEM.2019.09.005
  38. Schiødt FV, Ott P, Christensen E, Bondesen S. The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage. Clin Pharmacol Ther. 2002;71(4):221-225. doi:10.1067/MCP.2002.121857
  39. Filip AB, Berg SE, Mullins ME, Schwarz ES. Fomepizole as an adjunctive therapy for acetaminophen poisoning: cases reported to the toxicology investigators consortium (ToxIC) database 2015-2020. Clin Toxicol (Phila). 2022;60(9):1006-1011. doi:10.1080/15563650.2022.2070071
  40. Rampon G, Wartman H, Osmon S, Scalzo A. Use of fomepizole as an adjunct in the treatment of acetaminophen overdose: a case series. Toxicol Commun. 2020;4(1):1-4. doi:10.1080/24734306.2019.1705596
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