Acetaminophen toxicity

Background

• Includes Tylenol and numerous brands and products including acetaminophen

Maximal acetaminophen daily doses

• Adults: 4g/day
• Peds: 75mg/kg/day

Toxic dose

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

The 150 Rule

• Toxic dose is 150mg/kg
• Give NAC if level is >150 mcg/mL four hours post-ingestion
• Initial loading dose of NAC is 150mg/kg IV (140mg/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 = 1.5-2hrs
  • 40-60% - Glucuronidation
  • 20-40% - Sulfuronidation
  • 5-10% - Metabolism through CYP450 (Forms NAPQI)
• E - Conjugated and unconjugated excreted through kidneys

Toxicologic Pathophysiology

• 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 (>500mg/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 (7-8d) OR
• Deterioration to multi-organ failure and death OR
• Continued deterioration

Differential Diagnosis

Acute hepatitis

• Viral hepatitis
  • Hepatitis A
  • Hepatitis B
  • Hepatitis C
• Acute alcoholic hepatitis
• Acetaminophen toxicity
• Mushroom toxicity
  • Crotinarius mushrooms
  • Gyromitra mushrooms
  • Amanita mushrooms
• Ischemic hepatitis

Evaluation

Rumack-Matthew Nomogram (use correct units!)

Work-Up

• Acetaminophen (APAP) level
  • Obtain 4hrs post-ingestion
  • Obtaining <4hrs level or "arrival level" is of no diagnostic value
  • Obtaining multiple levels is rarely indicated in the absence of hepatotoxicity
• Chemistry
  • Metabolic acidosis seen with extremely large ingestion
• LFT
• PT/PTT/INR
• Aspirin levels and other co-ingestants

Rumack-Matthew Nomogram

• Only indicated for single, acute ingestion occurring <24hr 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-Mathew Nomogram is only for acute acetaminophen ingestions and not useful for chronic ingestions

<4hr 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 4-24hr 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 >24hr 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 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 325mg 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

Adult N-Acetylcysteine Dosing

See above guidelines for when to dose NAC

PO

• 140mg/kg PO load
• 70mg/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

References

Authors

Ross Donaldson, Jordan Swartz, Daniel Ostermayer, Manuel Celedon, Joe Carpenter, Joel Clinton Miller, Matthew Davey, Neil Young, Tim Davie, Bobak Zonnoor, Kevin Lu, Megan Kirch, Christopher Mathew, Allen Bookatz, Sabin Dang, Claire, Michael Holtz