Acetaminophen toxicity

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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)[1]
  • 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 [2] [3]

Stage 2 (days 2-3)

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

Stage 3 (days 3-4)

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

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
  • 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:

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

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
    • 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. [4]
    • 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 [5]

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) [6] [7]
  • Be aware NAC treatment may affect PT. May see a dose-dependent increase in PT following NAC in patients without hepatotoxicity. [8]

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[9]

King's College Criteria

  • Criteria for predicting fulminant hepatic failure, and thus referral to transplant center[10]
  • 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

Video

References

  1. Hendrickson RG, Bizovi KE. Acetaminophen. In: Flomenbaum NE, Goldfrank LR, Hoffman RS, et al, eds. Goldfrank’s Toxicologic Emergencies. 8th ed. New York: McGraw-Hill; 2002:523-543. (Textbook chapter)
  2. Roth B, Woo O, Blanc P. Early Metabolic Acidosis and Coma After Acetaminophen Ingestion. Ann Emerg Med. 1999;33(4):452-456.
  3. Zein JG, et al. Early anion gap metabolic acidosis in acetaminophen overdose. Am J Emerg Med. 2010;28:798-802.
  4. Heard KJ. Acetylcysteine for acetaminophen poisoning. N Eng J Med. 2008;359(3):285-292. (Review)
  5. Gosselin S, et al. Extracorporeal treatment for acetaminophen poisoning: Recommendations from the EXTRIP workgroup. Clin Tox. 2014;52:856-867.
  6. Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol-induced fulminant hepatic failure: a prospective controlled trial. BMJ. 1991;303(6809):1026-1029. (Prospective randomized controlled trial; 50 patients)
  7. Harrison PM, Keays R, Bray GP, et al. Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of N-acetylcysteine. Lancet. 1990;335(8705):1572- 1573. (Retrospective analysis; 100 patients)
  8. Wasserman GS, Garg U. Intravenous administration of Nacetylcysteine: interference with coagulopathy testing. Ann Emerg Med. 2004;44(5):546-547. (Letter)
  9. Mcgovern AJ, et al. Can AST/ALT ratio indicate recovery after acute paracetamol poisoning? Clin Toxciol. 2015; 53:164-167.
  10. Bailey B, et al. Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med. 2003; 31(1):299-305.