Acetaminophen toxicity

Background

• Recommended maximum total daily dose:
  • Adults: 4gm/day
  • Peds: 75mg/kg/day
• Toxic dose
  • >10gm or >200mg/kg as single ingestion or over 24hr period OR
  • >6gm or >150mg/kg per 24hr period x2d
• Peak serum levels seen within 2hr

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 (140mg/kg PO)

Pharmacology

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

Toxicology

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

1. Stage 1 (first 24hr)
   1. Mild N/V/malaise
   2. Hypokalemia (a/w high 4-hr level)
2. Stage 2 (days 2-3)
   1. Improvement in symptoms
   2. RUQ abd pain
   3. Elevated transaminases
   4. Elevated bilirubin, PT (if severe)
3. Stage 3 (days 3-4)
   1. Recurrence of N/V
   2. Hepatic failure
   3. Jaundice
   4. Coagulopathy
   5. Encephalopathy (esp w/ massive ingestions)
   6. Renal failure (1-2%; usually after hepatic failure is evident)
   7. Pancreatitis (rare)
4. Stage 4 (after day 5)
   1. Clinical improvement and recovery (7-8d) OR
   2. Deterioration to multi-organ failure and death OR
   3. Continued deterioration

Work-Up

1. APAP level
2. Chemistry
   1. Metabolic acidos seen w/ extremely large ingestion
3. LFT
4. PT/PTT/INR
5. Acetaminophen level: 4 hours post ingestion and repeat in 4 hours
6. ASA levels and other co-ingestants

Diagnosis

1. APAP level
   1. Obtain 4hrs post-ingestion
   2. Obtaining multiple levels is rarely indicated in the absence of hepatotoxicity
2. Nomogram (see below)
   1. Only indicated for single, acute ingestion occurring <24hr prior to presentation

Rumack-Matthew Nomogram

• Only indicated in single ingestion (ie. is not useful if chronic OD is suspected or if pt had multiple ingestions)
• Make sure you use the correct units!

Treatment

• Very important to identify time of ingestion

<4hr after ingestion

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

Between 4-24hr after ingestion

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

Unknown or >24hr after ingestion

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

Extended release overdose

• Extended-release acetaminophen (Tylenol ER) consists of acetaminophen 325 mg in immediate release (IR) form surrounding a matrix of acetaminophen 325 mg
  • 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.

N-acetylcysteine (NAC)

Background

1. Almost 100% effective if given <8 hr post-ingestion; less effective if 16-24 hr post-ingestion
2. May still be useful >24 hr post-ingestion, even with fulminant hepatic failure. Give NAC until LFTs improve (not until APAP level is 0)

Dosing:

PO

1. 140mg/kg PO load
2. 70mg/kg PO q4hr x17 doses additional; dilute to 5% soln

Side Effects

sulfur-smell causes nausea and vomiting. Consider mixing with juice or soda, in a cup with a lid and straw

IV

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

Side Effects

Anaphylactoid reaction but also associated with seizures, cerebral edema, & herniation.

King's College Criteria

• criteria for predicting fulminant hepatic failure, and thus referral to transplant center
• PPV 70-90% and sensitivity 69%
• includes:

1. pH<7.3 or lactate>3 at 12hrs after full fluid resuscitation, OR all of the following:
2. Cr>3.4
3. INR>6.5
4. grade 3 or 4 hepatic encephalopathy

• other predictors of APAP-induced hepatic failure include:

1. lactate>3.5 4hrs after fluid resusciation
2. phos>3.8 at 48hrs, OR
3. APACHE II >15

Disposition

• Consider discharge for asymptomatic pts who do not require NAC
• Psych consult if pt has suicidal ideation

External Links

• MDCalc - Acetaminophen Overdose & NAC Dosing
• MDCalc - King's College Criteria for Acetaminophen Toxicity