emDOCs Podcast – Episode 134: Acute Acetaminophen Toxicity

Today on the podcast, Rachel Bridwell and Brit Long cover acute acetaminophen toxicity, as well as some evidence updates.

Episode 134: Acute Acetaminophen Toxicity

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 referrals^2,3
  • 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 ingestion:⁵
  • >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 hepatotoxic^7,8
      • 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 occur in this 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 compounding^1,13
  • 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 necrosis^14,15
  • 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 hyperammonemia^16–18
    • Drowsiness, coma, lethargy, and agitation are all associated with mortality and poor outcomes (OR 23.95)¹⁹
•  Laboratory testing
  • 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 hepatoxicity^20,21
    • 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 acetaminophen^22,23
•  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

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) and consult toxicology
• Administer GI decontamination if able (activated charcoal, gastric lavage)
• 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
        • 150 mg/kg IV over 60 min
      • Stage 2 – Maintenance dose #1
        • 50 mg/kg over 4 hours
      • 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
        • 140 mg/kg
      • 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 with^28,29:
      • 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 acetaminophen^33,34
    • 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 undetectable^32,40
• 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:

• Acetaminophen is one of the most common causes of acute liver failure
• There are four stages, but massive overdose may present with acidosis, coma, and shock in stage 1
• 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
• Treatment includes resuscitation, poison center/toxicology consultation, and NAC
• 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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