Acetaminophen toxicity

Background

• Includes Tylenol and numerous brands and products including acetaminophen
• Now the most common cause of acute liver failure in the US

Maximal acetaminophen daily doses

• Adults: 4 g/day
• Peds: 75 mg/kg/day

Toxic dose

• >10 g or >200 mg/kg as single ingestion or over 24hr period OR
• >6 g or >150 mg/kg per 24hr period x 2days
• 200 mg/kg in healthy children 1-6 years of age

The 150 Rule

• Toxic dose is 150 mg/kg
• Give NAC if level is >150 mcg/mL four hours post-ingestion
• Initial loading dose of NAC is 150 mg/kg IV (140 mg/kg PO)

Mechanism of action

• Poorly understood
• Possibly through inhibition of Cyclooxygenase-3 (COX-3)
  • Decreases synthesis of prostaglandins
• Antipyresis through inhibition of hypothalamic heat center

Pharmacokinetics

• A - Rapid and near complete absorption
• D - Vd = 0.95 L/kg
• M - T 1/2 = 1.5-2 hrs
  • 40-60% - Glucuronidation
  • 20-40% - Sulfuronidation
  • 5-10% - Metabolism through CYP450/CYP2E1 (Forms NAPQI)
  • Metabolized by first-order kinetics
• E - Conjugated and unconjugated excreted through kidneys

Toxicologic Pathophysiology

• Acetaminophen is metabolized by sulfation and glucuronide conjugation. This process becomes overwhelmed in overdose and metabolism is shifted to the CYP 450 pathway generating toxic NAPQI.
• APAP toxic metabolite NAPQI usually quickly detoxified by glutathione stores in liver
  • In overdose, glutathione runs out, NAPQI accumulates → liver injury
• NAC increases availability of glutathione
  • NAC is a precursor

Clinical Features

Stage 1 (first 24hr)

• Mild nausea and vomiting/malaise
• Hypokalemia (associated with high 4-hr level)
• Massive Ingestion (>500 mg/kg) may present with acidemia, coma, hemodynamic changes shortly after ingestion and prior to hepatic necrosis

Stage 2 (days 2-3)

• Improvement in symptoms
• RUQ abdominal pain
• Elevated transaminases
• Elevated bilirubin, PT (if severe)

Stage 3 (days 3-4)

• Recurrence of nausea and vomiting
• Acute liver necrosis → liver failure
• Jaundice
• Coagulopathy
• Encephalopathy (esp with massive ingestions)
• Acute renal failure (1-2%; usually after hepatic failure is evident)
• Pancreatitis (rare)

Stage 4 (after day 5, up to 2 weeks)

• Clinical improvement and recovery (7-8 d) OR
• Deterioration to multi-organ failure and death OR
• Continued deterioration

Differential Diagnosis

Causes of acute hepatitis

• Acetaminophen toxicity (most common cause of acute liver failure in the US)
• Viral hepatitis
  • Hepatitis A
  • Hepatitis B
  • Hepatitis C
  • Hepatitis D
  • Hepatitis E
  • HSV
  • Epstein-Barr virus
  • Varicella zoster virus
• Toxoplasmosis
• Acute alcoholic hepatitis
• Toxins
  • Mushroom toxicity
  • Crotinarius mushrooms
    • Gyromitra mushrooms
    • Amanita mushrooms
• Ischemic hepatitis
• Autoimmune hepatitis
• Wilson's disease

Evaluation

Rumack-Matthew Nomogram (use correct units!)

Work-Up

• Acetaminophen (APAP) level
  • Obtain 4 hrs post-ingestion and compare level to Rumack-Matthew nomogram
  • Obtaining level between 2-4 hrs post ingestion is helpful if level is undetectable (essentially zero risk of progressing to toxic levels), but anything other than undetectable requires a repeat draw at 4 hrs
  • Obtaining multiple levels is rarely indicated in the absence of hepatotoxicity
• Chemistry
  • Metabolic acidosis seen with extremely large ingestion
  • Lactic acid and blood gas
• LFT
  • AST and ALT elevation more specific than GGT and alkaline phosphatase
  • AST levels > 1000 IU/L are more likely to result from acetaminophen poisoning than from chronic hepatitis or alcoholic liver disease
• PT/PTT/INR
• Aspirin levels and other co-ingestants

Rumack-Matthew Nomogram

• Only indicated for single, acute ingestion occurring <24 hr prior to presentation
  • Not useful for chronic ingestion (patients who take supratherapeutic doses for several days) or if time of ingestion is unknown
• Make sure you use the correct units!
• Dotted line should be used for those at higher-risk of liver toxicity (eg alcoholics, those on enzyme-inducing drugs)
• Co-ingestion of drugs that reduce GI motility should prompt repeating acetaminophen level at 8 hrs:
  • Opiates
  • Anticholinergics (diphenhydramine, etc.)

Management

Very important to identify time of ingestion. The Rumack-Matthew Nomogram is only for acute acetaminophen ingestions and not useful for chronic ingestions

<4 hr after ingestion

• GI decontamination
  • Activated Charcoal if <3 hr post-ingestion (no role for multidose activated charcoal)
  • Gastric Lavage if high-morbidity coingestants and <1 hr post-ingestion
• Send 4hr APAP level
  • Toxic level: Give NAC
  • Nontoxic level: No treatment necessary

Between 4-24 hr after ingestion

• Send APAP level
  • If level will be available within 8hr post-ingestion: wait for level before treating
  • If level will not be available within 8hr post-ingestion: do not wait for level before treating
    • Discontinue treatment if level returns non-toxic

Unknown or >24 hr after ingestion

• Consider GI decontamination for unknown ingestion time
• Give 1st dose of NAC
• Send APAP level, LFT, coags
  • APAP level >10 OR elevated transaminases? If yes then continue NAC
    • pH <7.3 or PT >100 or creatinine >3.3 or altered mental status? If yes refer to liver transplant unit
  • APAP level <10 and LFT both normal? If yes then stop NAC (treatment not indicated)

Chronic Ingestion

• Initiate NAC in any patient with evidence of ongoing hepatotoxicity (lft abnormalities) OR 'positive' tylenol level (>20 mcg/mL)
• If patient has normal LFT and 'negative' tylenol level (<20 mcg/mL), NAC treatment NOT required

Overdose in Pregnancy

• Both IV or oral NAC may be used in pregnant patients with Acetaminophen toxicity.
  • IV formulation may be preferred to increase fetal NAC concentrations

Extended release overdose

• Extended-release acetaminophen (Tylenol ER) consists of acetaminophen 325 mg in immediate release (IR) form surrounding a matrix of acetaminophen 325mg
  • Several studies show that the elimination of ER and IR APAP preparations is nearly identical after 4 hours. However, some case reports have documented APAP levels that are above the potential toxicity and treatment line on the nomogram as late as 11-14 hours after the ingestion of the ER preparation.
  • Recommended management includes the measurement of 4-, 6-, and 8-hour APAP concentrations. Begin NAC therapy if any level crosses above the nomogram treatment line. If the 6-hour level is greater than the 4-hour level, begin NAC therapy.

Massive Ingestion

• >500mg/kg
• May have early acidemia, coma, hemodynamic changes (does not necessarily indicate hepatic damage)
  • Supportive care (IVF, pressors, intubation PRN)
• Early consultation with poison control, prior to 4 hour level
• May consider early or increased NAC dosage, dialysis in extreme cases

NAC Treatment

Should begin if:

• The patient's history suggests:acetaminophen ingestion of ≥ 150mg/kg in children or 7.5 g in adults and the results of blood tests will not be available within 8 hours of the ingestion or
• Serum acetaminophen concentration falls on or above the Rumack-Matthew nomogram treatment line or
• While waiting for AST/ALT levels of a patient with a chronic overdose
  • Serum levels may not reach peak until up to 4 hours post-ingestion

Anaphylactoid reactions to IV NAC

• Generally the reactions are self limited with symptoms such as pruritis treated with Diphenhydramine. If angioedema develops NAC infusion should be stopped and restarted an hour after symptom resolution.

Adult N-Acetylcysteine Dosing

See above guidelines for when to dose NAC

PO

• Less preferred than IV route due to unpleasant taste and smell
• 140 mg/kg PO load
• 70 mg/kg PO q4hr x17 doses additional; dilute to 5% soln

IV

• Loading dose: 150mg/kg in 100 mL D5W over 60min
• Second (maintenance) dose: 50mg/kg in 250 mL D5W over 4hr
• Third dose: 100mg/kg in 500 mL D5W over 16hr

Comments

• Almost 100% effective if given <8 hr post-ingestion; less effective if 16-24 hr post-ingestion
• May still be useful >24 hr post-ingestion, even with fulminant hepatic failure. Give NAC until LFTs improve (not until APAP level is 0)
• Be aware NAC treatment may affect PT. May see a dose-dependent increase in PT following NAC in patients without hepatotoxicity.

Pediatric N-Acetylcysteine Dosing

For children there is a diluent added to the NAC so that there is no electrolyte and volume complications.

PO

• 140 mg/kg body weight, orally, once as a loading dose
• Maintenance Dose: 70 mg/kg body weight, orally, 4 hours after the loading dose and every 4 hours for 17 total doses, unless repeated acetaminophen assays reveal nontoxic levels

100 to 109 kg:

• Loading dose: 15 g (75 mL) in 225 mL diluent; total volume: 300 mL
• Maintenance Dose: 7.5 g (37 mL) in 113 mL diluent; total volume: 150 mL

90 to 99 kg:

• Loading dose: 14 g (70 mL) in 210 mL diluent; total volume: 280 mL
• Maintenance Dose: 7 g (35 mL) in 105 mL diluent; total volume: 140 mL

80 to 89 kg

• Loading dose: 13 g (65 mL) in 195 mL diluent; total volume: 260 mL
• Maintenance Dose: 6.5 g (33 mL) in 97 mL diluent; total volume: 130 mL

70 to 79 kg

• Loading dose: 11 g (55 mL) in 165 mL in diluent; total volume: 220 mL
• Maintenance Dose: 5.5 g (28 mL) in 82 mL diluent; total volume: 110 mL

60 to 69 kg

• Loading dose: 10 g (50 mL) in 150 mL diluent; total volume: 200 mL
• Maintenance Dose: 5 g (25 mL) in 75 mL diluent; total volume: 100 mL

50 to 59 kg

• Loading dose: 8 g (40 mL) in 120 mL diluent; total volume: 160 mL
• Maintenance Dose: 4 g (20 mL) in 60 mL diluent; total volume: 80 mL

40 to 49 kg

• Loading dose: 7 g (35 mL) in 105 mL diluent; total volume: 140 mL
• Maintenance Dose: 3.5 g (18 mL) in 52 mL diluent; total volume: 70 mL

30 to 39 kg

• Loading dose: 6 g (30 mL) in 90 mL diluent; total volume: 120 mL
• Maintenance Dose: 3 g (15 mL) in 45 mL diluent; total volume: 60 mL

20 to 29 kg

• Loading dose: 4 g (20 mL) in 60 mL diluent; total volume: 80 mL
• Maintenance Dose: 2 g (10 mL) in 30 mL diluent; total volume: 40 mL

Less than 20 kg

• Add 3 mL of diluent to each 1 mL (200 mg) of 20% acetylcysteine solution
• Loading dose: 140 g/kg
• Maintenance Dose: 70 g/kg

IV

for pediatrics (0-18) the addition of a dilution of NAC should be followed to avoid electrolyte and fluid problems

5 to 20 kg:

• Loading Dose: 150 mg/kg in 3 mL/kg diluent, infused over 1 hour
• Second Dose: 50 mg/kg in 7 mL/kg diluent, infused over 4 hours
• Third Dose: 100 mg/kg in 14 mL/kg diluent, infused over 16 hours

21 to 40 kg:

• Loading Dose: 150 mg/kg in 100 mL diluent, infused over 1 hour
• Second Dose: 50 mg/kg in 250 mL diluent, infused over 4 hours
• Third Dose: 100 mg/kg in 500 mL diluent, infused over 16 hours

Over 100 kg:

• Loading Dose: 15,000 mg in 200 mL diluent, infused over 1 hour
• Second Dose: 5,000 mg in 500 mL diluent, infused over 4 hours
• Third Dose: 10,000 mg in 1,000 mL diluent, infused over 16 hours

Disposition

• Consider discharge for asymptomatic patients who do not require NAC
• Admission if requiring NAC or other ingestions, injuries
• Transfer to transplant center based on above criteria
• Psych consult if patient has suicidal ideation
• In subacute toxicity, AST/ALT ratio of < 0.4 has sen of 99% for resolving hepatic injury

King's College Criteria

• Criteria for predicting fulminant hepatic failure, and thus referral to transplant center
• PPV 70-90% and sensitivity 69%
• Includes:
  • pH<7.3 or lactate>3 at 12hrs after full fluid resuscitation, OR all of the following:
  • Cr>3.4
  • INR>6.5
  • grade 3 or 4 Hepatic Encephalopathy

• Other predictors of APAP-induced hepatic failure include:
  • lactate >3.5 4hrs after fluid resusciation
  • phos >3.8 at 48hrs, OR
  • APACHE II >15

External Links

• MDCalc - Acetaminophen Overdose & NAC Dosing
• MDCalc - King's College Criteria for Acetaminophen Toxicity
• Merk Manual: Acetaminophen Poisoning
• Management of Acetaminophen Poisoning in the US and Canada: A Consensus Statement (2023)